Arylsulfonamides as antiviral agents

ABSTRACT

The present invention relates to novel sulphonamides of the general formula (I) 
                         
in which the substituents R 1 , R 2 , R 3 , R 4  and A and X are as defined in claim  1  and other claims, and also to processes for their preparation and to their use as antiviral agents, in particular against cytomegaloviruses.

The present invention relates to novel compounds, to processes for theirpreparation and to their use as medicaments, in particular as antiviralagents, in particular against cytomegaloviruses.

From WO 99/37291, compound2,2-dimethyl-N-[4-[[[4-(4-phenyl-2H-1,2,3-triazol-2-yl)phenyl]-sulphonyl]amino]phenyl]-propanamideis known as having antiviral action.

The present invention relates to compounds of the general formula (I)

in which

-   R² and R³ are identical or different and represent hydrogen,    hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy or represent a group of the formula

-    in which    -   R⁵, R⁶ and R⁷ are identical or different and each represents        hydrogen or (C₁–C₆)-alkyl which for its part may be substituted        by one or two substituents selected from the group consisting of        hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy,-   A represents five- or six-membered heteroaryl, which is attached to    the adjacent phenyl ring via a C atom and has one to three    heteroatoms selected from the group consisting of N, O and S,-   R¹ represents (C₆–C₁₀)-aryl, 5- to 10-membered heteroaryl or 5- to    10-membered heterocyclyl having in each case one to three    heteroatoms selected from the group consisting of N, O and S, where-   R¹ may be substituted by up to three substituents selected from the    group consisting of hydroxyl, amino, mono-(C₁–C₆)-alkylamino,    di-(C₁–C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁–C₆)-alkyl,    which for its part may be substituted by amino or hydroxyl,    (C₁–C₆)-alkoxy, phenyl, 5- or 6-membered heterocyclyl having up to    two heteroatoms selected from the group consisting of N, O and S, 5-    or 6-membered heteroaryl having one or more heteroatoms selected    from the group consisting of N, O and S, —C(O)—O—R⁸, —C(O)—NR⁹R¹⁰,    —NH—C(O)—R¹¹, —NH—C(O)—C(O)—R¹² and —NH—SO₂—R¹³,    -    where    -   R⁸, R⁹ and R¹⁰ are identical or different and each represents        hydrogen or (C₁–C₆)-alkyl, or    -   R⁹ and R¹⁰ together with the nitrogen atom to which they are        attached form a 5- or 6-membered heterocycle which may contain a        further nitrogen-or oxygen heteroatom and which may be mono- or        disubstituted by identical or different substituents from the        group consisting of (C₁–C₄)-alkyl, which for its part is        optionally substituted by hydroxyl or amino, amino, hydroxyl,        (C₁–C₄)-alkoxy, oxo, carboxyl and (C₁–C₄)-alkoxycarbonyl,    -   R¹¹ and R¹² are identical or different and each represents        trifluoromethyl, (C₁–C₆)-alkoxy, hydroxyl, or represents        (C₁–C₆)-alkyl, which is optionally mono- or disubstituted by        identical or different constituents from the group consisting of        amino, (C₁–C₆)-alkoxycarbonylamino, mono-(C₁–C₆)-acylamino,        hydroxyl, amidino, guanidino, (C₁–C₆)-alkoxycarbonyl, carboxyl        and phenyl, and    -   R¹³ represents (C₁–C₆)-alkyl or (C₆–C₁₀)-aryl which may in each        case be substituted by halogen, amino, hydroxyl, (C₁–C₄)-alkoxy        or (C₁–C₄)-alkyl,-   R⁴ represents (C₁–C₆)-alkyl which may be substituted up to three    times by identical or different substituents from the group    consisting of amino, hydroxyl, halogen, (C₁–C₆)-alkoxy,    (C₁–C₅)-alkanoyloxy and phenyl, which for its part is optionally    mono- or disubstituted by identical or different substituents from    the group consisting of halogen, nitro, cyano, amino and hydroxyl,    -   represents (C₃–C₇)-Cycloalkyl which may be substituted up to        three times by identical or different substituents from the        group consisting of amino, hydroxyl, halogen, (C₁–C₆)-alkoxy and        (C₁–C₆)-alkyl, which for its part is optionally substituted up        to three times by identical or different substituents from the        group consisting of amino, hydroxyl, halogen and (C₁–C₆)-alkoxy,        or represents (C₆–C₁₀)-aryl which is optionally mono- or        disubstituted by identical or different substituents from the        group consisting of halogen, nitro, cyano, amino and hydroxyl,-   and in which-   X represents oxygen or sulphur,-   and in which nitrogen-containing heterocycles may also be present as    N-oxides,-   and their tautomers, stereoisomers, stereoisomer mixtures and their    pharmacological acceptable salts.

In the context of the invention, (C₁–C₆)-alkyl represents astraight-chain or branched alkyl radical having 1 to 6 carbon atoms. Thefollowing radicals may be mentioned by way of example: methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and n-hexyl.

In the context of the invention, (C₃–C₇)-cycloalkyl represents acycloalkyl group having 3 to 7 carbon atoms. The following radicals maybe mentioned by way of example: cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

In the context of the invention, (C₁–C₆)-alkoxy represents astraight-chain or branched alkoxy radical having 1 to 6 carbon atoms.The following radicals may be mentioned by way of example: methoxy,ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.Preference is given to methoxy and ethoxy.

In the context of the invention, (C₆–C₁₀)-aryl represents an aromaticradical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyland naphthyl.

In the context of the invention, aralkyl represents (C₆–C₁₀)-aryl, whichfor its part is attached to (C₁–C₄)-alkyl. Preference is given tobenzyl.

In the context of the invention, mono-(C₁–C₆)-alkylamino represents anamino group having a straight-chain, branched or cyclic alkylsubstituent having 1 to 6 carbon atoms. The following radicals may bementioned by way of example: methylamino, ethylamino, n-propylamino,isopropylamino, cyclopropylamino, t-butylamino, n-pentylamino,cyclopentylamino and n-hexylamino.

In the context of the invention, di-(C₁–C₆)-alkylamino represents anamino group having two identical or different straight-chain, branchedor cyclic alkyl substituents, having in each case 1 to 6 carbon atoms.The following radicals may be mentioned by way of example:N,N-dimethylamino, N,N-diethyl amino, N-ethyl-N-methylamino,N-methyl-N-n-propylamino, N-methyl-N-cyclopropylamino,N-isopropyl-N-n-propyl-amino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

In the context of the invention, (C₁–C₆)-alkoxycarbonyl represents astraight-chain or branched alkoxy-radical having 1 to 6 carbon atoms,which is attached via a carbonyl group. Preference is given to astraight-chain or branched alkoxycarbonyl radical having 1 to 4 carbonatoms. The following radicals may be mentioned by way of example and byway of preference: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl and t-butoxycarbonyl.

In the context of the invention, (C₁–C₆)-alkoxycarbonylamino representsan amino group having a straight-chain or branched alkoxycarbonylsubstituent which has 1 to 6 carbon atoms in the alkoxy radical and isattached via the carbonyl group. Preference is given to analkoxycarbonylamino radical having 1 to 4 carbon atoms in the alkoxyradical. The following radicals may be mentioned by way of example andby way of preference: methoxycarbonylamino, ethoxycarbonylamino,n-propoxy-carbonylamino and t-butoxycarbonylamino.

In the context of the invention, mono-(C₁–C₆)-acylamino represents anamino group having a straight-chain or branched alkanoyl substituentwhich has 1 to 6 carbon atoms and is attached via the carbonyl group.Preference is given to a monoacylamino radical having 1 or 2 carbonatoms. The following radicals may be mentioned by way of example and byway of preference: formamido, acetamido, propionamido, n-butyramido andpivaloylamido.

In the context of the invention, (C₁–C₅)-alkanoyloxy preferablyrepresents a straight-chain or branched alkyl radical having 1 to 5carbon atoms which carries a doubly attached oxygen atom in the1-position and which is attached in the 1-position via a further oxygenatom. Preference is given to a straight-chain or branched alkanoyloxyradical having 1 to 3 carbon atoms. The following radicals may bementioned by way of example and by way of preference: acetoxy,propionoxy, n-butyroxy, i-butyroxy and pivaloyloxy.

In the context of the invention, halogen generally represents fluorine,chlorine, bromine and iodine. Preference is given to fluorine, chlorineand bromine. Particular preference is given to fluorine and chlorine.

In the context of the invention, 5- to 10-membered heteroaryl represents5- to 10-membered hetero-containing aromatic rings which may contain 1to 4 heteroatoms selected from the group consisting of O, S and N,including, for example: pyridyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolicenyl, indolyl,benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl,naphthyridinyl, quinazolinyl, etc.

In the context of the invention, 5- to 10-membered or 5- or 6-memberedsaturated or partially unsaturated heterocyclyl having up to 3heteroatoms from the croup consisting of S, N and O generally representsa mono- or bicyclic heterocycle which may contain one or more doublebonds and which is attached via a ring carbon atom or a ring nitrogenatom. The following radicals may be mentioned by way of example:tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, piperidin-1-yl,piperidin-3-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl,piperazin-1-yl, morpholin-1-yl, azepin-1-yl, 1,4-diazepin-1-yl.Preference is given to piperidinyl, morpholinyl and pyrrolidinyl.

1,2,4-Oxadiazole which is attached via the 3- or 5-position representsan oxadiazole which is attached to the phenylsulphonamide via the ringcarbon atom in the 3- or 5-position.

In the context of the invention, the preferred salts arepharmacologically acceptable salts of the compounds according to theinvention.

Pharmacologically acceptable salts of the compounds according to theinvention may be acid addition salts of the compounds according to theinvention with mineral acids, carboxylic acids or sulphonic acids.Particular preference is given, for example, to salts with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

However, salts that may be mentioned include salts with customary bases,such as, for example, alkali metal salts (for example sodium salts orpotassium salts), alkaline earth metal salts (for example calcium saltsor magnesium salts) or ammonium salts, derived from ammonia or organicamines, such as, for example, diethylamine, triethylamine,ethyldiusopropylamine, procaine, dibenzylamine, N-methylmorpholine,dihydroabietylamine, 1-ephenamine or methylpiperidine, or derived fromnatural amino acids, such as, for example, glycine, lysine, arginine orhistidine.

The compounds according to the invention may exist in stereoisomericforms which are either like image and mirror image (enantiomers) orwhich are not like image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers and to their respectivemixtures. The racemic forms can, like the diastereomers, be separatedinto the stereoisomerically uniform components in a manner known per se.

In addition, the invention also embraces prodrugs of the compoundsaccording to the invention. According to the invention, prodrugs arederivatives of the compounds of the general formula (I) which for theirpart may be biologically less active or even inactive, but, followingadministration, are converted under physiological conditions into thecorresponding biologically active form (for example metabolically,solvolytically or in another manner).

The invention also relates to compounds of the general formula (I),

in which

-   R² and R³ are identical or different and represent hydrogen,    hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy or represent a group of the formula

-    in which    -   R⁵, R⁶ and R⁷ are identical or different and each represents        hydrogen or (C₁–C₆)-alkyl, which for its part may be substituted        by one or two substituents selected from the group consisting of        hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy,-   A represents five- or six-membered heteroaryl, which is attached to    the adjacent phenyl ring via a C atom and has one to three    heteroatoms selected from the group consisting of N, O and S,-   R¹ represents (C₆–C₁₀)-aryl, 5- to 10-membered heteroaryl or 5- to    10-membered heterocyclyl having in each case one to three    heteroatoms selected from the group consisting of N, O and S, where-   R¹ may be substituted by up to three substituents selected from the    group consisting of hydroxyl, amino, mono-(C₁–C₆)-alkylamino,    di-(C₁–C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁–C₆)-alkyl,    which for its part may be substituted by amino or hydroxyl,    (C₁–C₆)-alkoxy, phenyl, 5- or 6-membered heteroaryl having one or    more heteroatoms selected from the group consisting of N, O and S,    —C(O)—O—R⁸, —C(O)—NR⁹R¹⁰ and —NH—C(O)—R¹¹, where    -   R⁸, R⁹ and R¹⁰ are identical or different and each represents        hydrogen or (C₁–C₆)-alkyl, and    -   R¹¹ represents (C₁–C₆)-alkyl which is optionally mono- or        disubstituted by identical or different substituents from the        group consisting of amino, hydroxyl, guanidino, carboxyl and        phenyl,-   R⁴ represents (C₁–C₆)-alkyl which may be substituted up to three    times by identical or different substituents from the group    consisting of amino, hydroxyl, halogen, (C₁–C₆)-alkoxy and phenyl,    which for its part is optionally mono- or disubstituted by identical    or different substituents from the group consisting of halogen,    nitro, cyano, amino and hydroxyl,    -   represents (C₃–C₇)-cycloalkyl which may be substituted up to        three times by identical or different substituents from the        group consisting of amino, hydroxyl, halogen, (C₁–C₆)-alkoxy and        (C₁–C₆)-alkyl, which for its part is optionally substituted up        to three times by identical or different substituents from the        group consisting of amino, hydroxyl, halogen and (C₁–C₆)-alkoxy,    -   or represents (C₆–C₁₀)-aryl which is optionally mono- or        disubstituted by identical or different substituents from the        group consisting of halogen, nitro, cyano, amino and hydroxyl,    -   and in which-   X represents oxygen or sulphur,-   and in which nitrogen-containing heterocycles may also be present as    N-oxides,-   and their tautomers, stereoisomers, stereoisomer mixtures and their    pharmacologically acceptable salts.

The invention preferably relates to compounds of the general formula(I),

in which

-   R² and R³ are identical or different and represent hydrogen,    hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy or represent a group of the formula

-    in which    -   R⁵, R⁶ and R⁷ are identical or different and each represents        hydrogen or (C₁–C₆)-alkyl, which for its part may be substituted        by one or two substituents selected from the group consisting of        hydroxyl, halogen, cyano, trifluoromethyl and trifluoromethoxy,-   A represents five- or six-membered heteroaryl, which is attached to    the adjacent phenyl ring via a C atom and has one to three    heteroatoms selected from the group consisting of N, O and S,-   R¹ represents (C₆–C₁₀)-aryl, 5- to 10-membered heteroaryl or 5- to    10-membered heterocyclyl having in each case one to three    heteroatoms selected from the group consisting of N, O and S, where-   R¹ may be substituted by up to three substituents selected from the    group consisting of hydroxyl, amino, mono-(C₁–C₆)-alkylamino,    di-(C₁–C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁–C₆)-alkyl,    which for its part may be substituted by amino or hydroxyl,    (C₁–C₆)-alkoxy, phenyl, 5- or 6-membered heteroaryl having one or    more heteroatoms selected from the group consisting of N, O and S,    —C(O)—O—R⁸, —C(O)—NR⁹R¹⁰ and —NH—C(O)—R¹¹, where    -   R⁸, R⁹ and R¹⁰ are identical or different and each represents        hydrogen or (C₁–C₆)-alkyl, and    -   R¹¹ represents (C₁–C₆)-alkyl, which is optionally mono- or        disubstituted by identical or different substituents from the        group consisting of amino, hydroxyl, guanidino, carboxyl and        phenyl,-   R⁴ represents (C₁–C₆)-alkyl which may be substituted up to three    times by identical or different substituents from the group    consisting of amino, hydroxyl, halogen, (C₁–C₆)-alkoxy and phenyl,    which for its part is optionally mono- or disubstituted by identical    or different substituents from the group consisting of halogen,    nitro, cyano, amino and hydroxyl,    -   represents (C₃–C₇)-cycloalkyl which may be substituted up to        three times by identical or different substituents from the        group consisting of amino, hydroxyl, halogen, (C₁–C₆)-alkoxy and        (C₁–C₆)-alkyl, which for its part is optionally substituted up        to three times by identical or different substituents from the        group consisting of amino, hydroxyl, halogen and (C₁–C₆)-alkoxy,    -   or represents (C₆–C₁₀)-aryl which is optionally mono- or        disubstituted by identical or different substituents from the        group consisting of halogen, nitro, cyano, amino and hydroxyl,-   and in which-   X represents oxygen,-   and in which nitrogen-containing heterocycles may also be present as    N-oxides,-   and their tautomers, stereoisomers, stereoisomer mixtures and their    pharmacologically acceptable salts.

The invention preferably also relates to compounds of the generalformula (I),

in which

-   R² and R³ are identical or different and represent hydrogen or    halogen,-   A represents the radical (A-I)

-    which is attached to the adjacent phenyl ring via one of the carbon    atoms in position 3 or 5,    -   and in which-   Y represents oxygen or sulphur, or-   A represents the radical (A-II)

-    which is attached to the adjacent phenyl ring via one of the carbon    atoms in position 2 or 5,    -   and in which    -   Y represents oxygen or sulphur,-   R¹ represents 5- to 10-membered heteroaryl or 5- or 10-membered    heterocyclyl having in each case up to three heteroatoms selected    from the group consisting of N, O and S, or represents phenyl, where-   R¹ may be substituted by one to three substituents selected from the    group consisting of (C₁–C₄)-alkyl, which for its part is optionally    substituted by hydroxyl or amino, hydroxyl, oxo, halogen, amino,    mono-(C₁–C₄)-alkylamino, di-(C₁–C₄)-alkylamino and —NH—C(O)—R¹¹,    where    -   R¹¹ represents (C₁–C₆)-alkyl which is optionally mono- or        disubstituted by identical or different substituents from the        group consisting of amino, hydroxyl, guanidino and carboxyl,-   R⁴ represents (C₁–C₄)-alkyl which may be substituted up to three    times by identical or different substituents from the group    consisting of amino, hydroxyl, fluorine, chlorine and    (C₁–C₄)-alkoxy,    -   represents (C₃–C₅)-cycloalkyl, which may be substituted up to        three times by identical or different substituents from the        group consisting of amino, hydroxyl, fluorine, chlorine,        (C₁–C₄)-alkoxy and (C₁–C₄)-alkyl, which for its part is        optionally substituted up to three times by identical or        different substituents from the group consisting of amino,        hydroxyl, fluorine, chlorine and (C₁–C₄)-alkoxy,-   and in which-   X represents oxygen or sulphur,-   and in which nitrogen-containing heterocycles may also be present as    N-oxides,-   and their tautomers, stereoisomers, stereoisomer mixtures and their    pharmacologically acceptable salts.

The invention particularly preferably relates to compounds of thegeneral formula (I),

in which

-   R² and R³ are identical or different and represent hydrogen or    halogen,-   A represents the radical (A-I)

-    which is attached to the adjacent phenyl ring via one of the carbon    atoms in position 3 or 5,    -   and in which    -   Y represents oxygen or sulphur, or-   A represents the radical (A-II)

-    which is attached to the adjacent phenyl ring via one of the carbon    atoms in position 2 or 5,    -   and in which    -   Y represents oxygen or sulphur,-   R¹ represents 5- to 10-membered heteroaryl or 5- or 10-membered    heterocyclyl having in each case up to three heteroatoms selected    from the group consisting of N, O and S, or represents phenyl, where-   R¹ may be substituted by one to three substituents selected from the    group consisting of (C₁–C₄)-alkyl, which for its part is optionally    substituted by hydroxyl or amino, hydroxyl, oxo, halogen, amino,    mono-(C₁–C₄)-alkylamino, di-(C₁–C₄)-alkylamino and —NH—C(O)—R¹¹,    where    -   R¹¹ represents (C₁–C₆)-alkyl which is optionally mono- or        disubstituted by identical or different substituents from the        group consisting of amino, hydroxyl, guanidino and carboxyl,-   R⁴ represents (C₁–C₄)-alkyl which may be substituted up to three    times by identical or different substituents from the group    consisting of amino, hydroxyl, fluorine, chlorine and    (C₁–C₄)-alkoxy, or    -   represents (C₃–C₅)-cycloalkyl which may be substituted up to        three times by identical or different substituents from the        group consisting of amino, hydroxyl, fluorine, chlorine,        (C₁–C₄)-alkoxy and (C₁–C₄)-alkyl, which for its part is        optionally substituted up to three times by identical or        different substituents from the group consisting of amino,        hydroxyl, fluorine, chlorine and (C₁–C₄)-alkoxy,-   and in which-   X represents oxygen,-   and their tautomers, stereoisomers, stereoisomer mixtures and their    pharmacologically acceptable salts.

The invention particularly preferably relates to compounds of thegeneral formula (I),

in which

-   R² and R³ represent hydrogen,-   A represents one of the radicals

-    R¹ represents a radical selected from the group consisting of    phenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl,    isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and    indolyl, where    -   R¹ may be substituted by one or two substituents selected from        the group consisting of methyl, aminomethyl, hydroxyl, bromine,        chlorine, fluorine, amino, dimethylamino and —NH—C(O)—R¹¹, where        -   R¹¹ represents (C₁–C₆)-alkyl which is optionally mono- or            disubstituted by identical or different substituents from            the group consisting of amino, hydroxyl, guanidino and            carboxyl,    -   R⁴ represents tert-butyl which is optionally substituted up to        three times by identical or different substituents from the        group consisting of hydroxyl, fluorine and chlorine, or        -   represents cyclopropyl or cyclobutyl which are substituted            by methyl, which for its part is optionally substituted by            hydroxyl, fluorine or chlorine,    -   and in which    -   X represents oxygen,    -   and in which nitrogen-containing heterocycles may also be        present as N-oxides,    -   and their tautomers, stereoisomers, stereoisomer mixtures and        their pharmacologically acceptable salts.

With particular preference, the invention relates to compounds of thegeneral formula (I),

in which

-   R² and R³ represent hydrogen,-   A represents one of the radicals

-   R¹ represents a radical selected from the group consisting (of    phenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl,    isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and    indolyl, where-   R¹ may be substituted by one or two substituents selected from the    group consisting of methyl, aminomethyl, hydroxyl, bromine,    chlorine, fluorine, amino, dimethylamino and —NH—C(O)—R¹¹, where    -   R¹¹ represents (C₁–C₆)-alkyl which is optionally mono- or        disubstituted by identical or different substituents from the        group consisting of amino, hydroxyl, guanidino and carboxyl,-   R⁴ represents tert-butyl which is optionally substituted up to three    times by identical or different substituents from the group    consisting of hydroxyl fluorine and chlorine, or    -   represents cyclopropyl or cyclobutyl which are substituted by        methyl, which for its part is optionally substituted by        hydroxyl, fluorine- or chlorine,-   and in which-   X represents oxygen.

In a preferred embodiment, the invention relates to compounds of thegeneral formula (Ia)

in which

-   R¹, R⁴, A and X are as defined above, and-   R² and R³ are identical or different and represent hydrogen,    hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,    (C₁–C₆)-alkyl or (C₁–C₆)-alkoxy.

In a further preferred embodiment, the invention relates to compounds ofthe general formula (I),

in which

-   R⁴ represents one of the radicals

In a further preferred embodiment, the invention relates to compounds ofthe general formula (I),

in which

-   A represents 1,2,4-oxadiazole which is attached via the 3-position.

Very particularly preferred compounds of the present invention aresulphonamides which are selected from the group of the followingcompounds:

The invention furthermore relates to processes for preparing compoundsof the general formula (I), which are characterized in that

-   [A] nitro-anilines of the general formula [A-1]

-    in which    -   R³ has the meaning given above,    -   are reacted with compounds of the general formula [A-2]

-   -    in which    -   X and R⁴ have one of the meanings given above, and    -   Q represents a leaving group, for example halogen, preferably        chlorine or bromine,    -   in inert solvents in the presence of a base to give compounds of        the general formula [A-3]

-   -    in which    -   X, R³ and R⁴ have one of the meanings given above, and

-   [B] the nitro-aromatic compounds of the general formula [A-3] are    reduced in inert solvents, for example in the presence of transition    metal catalysts and hydrogen, to aromatic amines of the general    formula [B-1]

-    in which    -   X, R³ and R⁴ have one of the meanings given above, and-   [C] amines of the general formula [B-1] are reacted with sulphonic    acid derivatives of the general formula [C-1]

-    in which    -   R² has the meaning given above, and    -   Z represents a leaving group, for example halogen, preferably        chlorine or bromine,    -   in inert solvents, in the presence of a base, to give compounds        of the general formula [C-2]

-   -    in which    -   X, R², R³ and R⁴ have one of the meanings given above, and

-   [D] the nitriles of the general formula [C-2] are reacted in polar    protic solvents, for example alcohols, at elevated temperature,    preferably the boiling point of the solvent, in the presence of a    base with hydroxylamine to give amidoximes of the general formula    [D-1]

-    in which    -   X, R², R³ and R⁴ have one of the meanings given above, and-   [E] amidoximes of the general formula [D-1] are acylated with a    carboxylic acid of the general formula [E-1]    R¹—COOH  [E-1]-    in which    -   R¹ has the meaning given above,        in the presence of a condensing agent, for example        benzotriazolyl-N-oxi-tris(dimethylamino)phosphonium        hexafluorophosphate (PyBOP), or other activating agents known        from peptide chemistry, and also acid chlorides, and a base in a        polar aprotic solvent, for example tetrahydrofuran, and the        acylated amidoxime is isolated as a crude product and then        cyclized in a high-boiling polar solvent, for example DMF, at        elevated temperature, to give the 1,2,4-oxadiazole.

The process according to the invention for preparing 1,2,4-oxadiazolesattached via the 3-position is illustrated in an exemplary manner by theformula scheme below:

The invention furthermore relates to processes for preparing compoundsof the general formula (I), characterized in that

-   [F] sulphonyl halides of the general formula [F-1]

-    in which    -   R² and Z have the meaning given above, and    -   R^(F-1) represents (C₁–C₄)-alkyl, aralkyl or a carboxylic acid        protective group,    -   are reacted in the presence of a base with anilines of the        general formula [B-1] to give sulphonamides of the general        formula [F-2]

-   -    in which    -   R^(F-1), R², R³, R⁴ and X have the meaning given above,    -   and the group R^(F-1) is then cleaved off from the compounds of        the general formula [F-2], for example in the presence of        hydroxyl anions, giving sulphonamides of the general formula        [F-3],

-   -    and

-   [G] amid-oximes of the general formula [G-1]

-    in which    -   R¹ has the meaning given above,    -   are condensed with compounds of the general formula [F-3] to        give compounds of the general formula [G-2],

-   -    in which    -   R¹, R², R³, R⁴ and X have the meaning given above, and

-   [H] compounds of the general formula [G-2] are cyclized thermally to    give the 1,2,4-oxadiazoles, attached via the 5-position, of the    general formula [H-1]

-    in which    -   R¹, R², R³, R⁴ and X have the meaning given above.

The compounds according to the invention can be prepared, for example,according to the formula scheme below:

Solvents suitable for all process steps are the customary inert solventswhich do not change under the reaction conditions. These preferablyinclude organic solvents, such as ethers, for example diethyl ether,glycol monomethyl ether or glycol dimethyl ether, dioxane ortetrahydrofuran, or alcohols, such as methanol, ethanol, n-propanol,iso-propanol, n-butanol or tert-butanol, or hydrocarbons, such asbenzene, toluene, xylene, cyclohexane or mineral oil fractions, orhalogenated hydrocarbons, such as methylene chloride, chloroform orcarbon tetrachloride, or dimethyl sulphoxide, dimethylformamide,hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine orpicoline. It is also possible to use mixtures of the solvents mentioned,if appropriate also with water. Particular preference is given tomethylene chloride, tetrahydrofuran, dioxane and dioxane/water and inparticular to the solvents mentioned in the section “GeneralProcedures”.

Suitable bases are organic amines, such as tri-(C₁–C₆)-alkylamines, forexample triethylamine, or heterocycles, such as pyridine,methylpiperidine, piperidine or N-methylmorpholine. Preference is givento triethylamine and pyridine.

The bases are generally employed in an amount of from 0.1 mol to 5 mol,preferably from 1 mol to 3 mol, in each case based on 1 mol of thecompounds of the general formulae [A-1], [B-1], [C-2], [D-1] and [E-1].

The reactions can be carried out at atmospheric pressure, but also atelevated or reduced pressure (for example from 0.5 to 3 bar). Ingeneral, the reactions are carried out at atmospheric pressure.

The reactions are carried out in a temperature range of from 0° C. to150° C., preferably from 0° C. to 30° C., and at atmospheric pressure.The conversion of the compounds [G-2] into [H-1] is carried out atelevated temperature, preferably at temperatures above 100° C.

The reductions can generally be-carried out using hydrogen in inertorganic solvents, such as dimethylformamide, alcohols, ethers or aceticesters, or mixtures thereof, using catalysts such as Raney-nickel,palladium, palladium on carbon or platinum, or using hydrides orboranes, or using inorganic reducing agents, such as, for example,tin(II) chloride, in inert solvents, if appropriate in the presence of acatalyst. Preference is given to palladium on carbon.

The reaction can be carried out at atmospheric or at elevated pressure(for example from 1 to 5 bar). In general, the reaction is carried outat atmospheric pressure. Hydrogenations are preferably carried out underelevated pressure, in general at 3 bar.

The reductions are generally carried out in a temperature range of from0° C. to +60° C., preferably at from +10° C. to +40° C.

Solvents which are suitable for the acylation are customary organicsolvents which do not change under the reaction conditions. Thesepreferably include ethers, such as diethyl ether, dioxane,tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, or triethylamine, pyridine,dimethylformamide, acetonitrile or acetone. It is also possible to usemixtures of the solvents mentioned. Preference is given todichloromethane, tetrahydrofuran and pyridine.

The acylation is carried out in the solvents listed above, attemperatures of from 0° C. to +150° C., preferably at from roomtemperature to +100° C., and at atmospheric pressure.

The compounds of the general formulae [A-1], [A-2], [C-1], [E-1], [F-1]and [G-1] are known per se or can be prepared by methods known from theliterature.

Further compounds of the general formula (I) in which A represents a1,3,4-oxadiazole can be prepared, for example, on a polymeric supportusing the IRORI system according to the “Split & Mix” method, as shownbelow in Scheme 4:

Compounds of the general formula (I) are furthermore obtained, forexample, by a process according to Scheme 5 which is carried out in amixed procedure involving solid-phase synthesis and synthesis insolution.

The processes shown in Schemes 4 and 5 also permit the preparation offurther compounds of the general formula (I) according to the inventionin which

-   X represents oxygen and-   A represents the radical (A-II)

-    which is attached to the adjacent phenyl ring via one of the carbon    atoms in position 2 or 5,    -   and in which    -   Y represents oxygen,-   by cyclizing hydrazides of the general formula [H-2]

-    in which X, R¹, R², R³, R⁴ have one of the meanings given above,    and-   FH represents hydrogen, an amino protective group or a polymeric    support, with elimination of water, to give the compounds of the    general formula (I).

They further permit the preparation of compounds of the general formula(I) in which

-   X represents oxygen and-   A represents the radical (A-II)

-    which is attached to the adjacent phenyl ring via one of the carbon    atoms of position 2 or 5,    -   and in which    -   Y represents sulphur,-   by cyclizing hydrazides of the general formula [H-3]

-    in which R¹, R², R³ are as defined above,-   FH represents hydrogen, an amino protective group or a polymeric    support, and-   R^(4′) represents (C₁–C₆)-alkoxy, (C₁–C₆)-alkenoxy or aralkoxy,-   in the presence of a thio donor, preferably Lawesson's reagent, to    give compounds of the general formula (I) in which Y represents    sulphur, then removing group —C(O)—R^(4′) and finally reacting with    compounds of the general formula

in which R⁴ and Q are as defined above.

The compounds of the general formula (I) according to the invention showa surprising range of actions which could not have been predicted. Theyshow an antiviral action on representatives of the group of the Herpesviridae, in particular on human cytomegalovirus (HCMV). They are thussuitable for the treatment and prophylaxis of disorders caused by Herpesviridae, in particular disorders caused by human cytomegaloviruses.

Owing to their particular properties, the compounds of the generalformula (1) can be used for preparing medicaments suitable for theprophylaxis or treatment of diseases, in particular viral disorders.

Owing to their properties, the compounds according to the invention areuseful active compounds for the treatment and prophylaxis of infectionsby human cytomegaloviruses and disorders caused by these infections.Examples of areas of indication which may be mentioned are:

-   1) Treatment and prophylaxis of HCMV infections in AIDS patients    (retinitis, pneumonitis, gastrointestinal infections).-   2) Treatment and prophylaxis of cytomegalovirus infections in bone    marrow and organ transplant patients who often suffer    life-threatening HCMV pneumonitis or encephalitis, or    gastrointestinal or systemic HCMV infections.-   3) Treatment and prophylaxis of HCMV infections in neonates and in    infants.-   4) Treatment of an acute HCMV infection in pregnant women.-   5) Treatment of HCMV infections in immunosuppressed patients    suffering from cancer and undergoing cancer therapy.

The novel active compounds can be used on their own and, if required,also in combination with other antiviral active compounds, such as, forexample, gancycloyir or acylovir.

Descriptions of Biological Tests:

In Vitro Action:

Anti-HCMV (Anti-Human Cytomegalovirus) and anti-MCMV (Anti-MurineCytomegalovirus) cytopathogenicity tests:

The test compounds were employed as 50 millimolar (mM) solutions indimethyl sulphoxide (DMSO). Ganciclovir, foscarnet and cidofovir servedas reference compounds. Following the addition of in each case 2 μl ofthe 50, 5, 0.5 and 0.05 mM DMSO stock solutions to in each case 98μ ofcell culture medium in row 2 A-H, in duplicate determinations, 1:2dilutions with in each case 50 μl of medium were prepared up to row 11of the 96-well plate. The wells in rows 1 and 12 each contained 50 μl ofmedium. 150 μl of a suspension of 1×10⁴ cells (human lung fibroblasts[HELF]) (row 1=cell control) or, in rows 2–12, a mixture ofHCMV-infected and non-infected HELF cells (M.O.I.=0.001–0.002), i.e. 1–2infected cells per 1000 non-infected cells, were then pipetted into eachof the wells. Row 12 (without substance) served as virus control. Thefinal test concentrations were 250–0.0005 μM. The plates were incubatedat 37° C./5% CO₂ for 6 days, i.e. until all cells in the virus controlshad been infected (100% cytopathogenic effect [CPE]). The wells werethen fixed and stained by adding a mixture of Formalin and Giemsa Stain(30 minutes), washed with doubly distilled water and dried in a dryingcabinet at 50° C. The plates were then evaluated visually using anoverhead microscope (plaque multiplier from Technomara).

From the test plates, the following data were determined:

CC₅₀ (HELF)=substance concentration in μM at which, compared to theuntreated cell control, no visible cytostatic effects on the cells werenoticeable;

EC₅₀ (HCMV)=substance concentration in μM which inhibits the CPE(cytopathic effect) by 50% compared to the untreated virus control;

SI (selectivity index)=CC₅₀ (HELF)/EC50 (HCMV).

Compared to the process described above for HCMV, the anti-MCMV test wascarried out with the following changes: a cell-free virus suspension wasmixed with a concentrated cell suspension (3T3 mouse cells) andincubated for 15 minutes for adsorption of the viruses, and thesuspension was then diluted with medium to 1.3×10⁵ cells/ml with a finalmultiplicity of infection (M.O.I.) of from 0.05–0.1, and in each case150 μl were dispensed into the wells. The incubation time was 5 days.

Representative activity data for the compounds according to theinvention are given in Table 1:

TABLE 1 HELF 3T3 MCMV Example CC₅₀ HCMV EC₅₀ SI CC₅₀ EC₅₀ SI No. [μM][μM] HCMV [μM] [μM] MCMV 1 110 0.055 2000 33 0.019 1737 2 <16 0.05 <3200.9 0.045 20 3 <140 0.018 <7778 23 0.008 2875 4 >63 0.01 >6300 11 0.015733 5 >16 0.016 >1000 >31 0.014 >2214 6 39 0.02 2053 2.9 0.041 71 7 470.025 1880 12 0.025 480 8 >2.2 0.02 >110 >3.9 0.024 >163 9 39 0.018 21674 0.068 59 10 >3.9 0.008 >488 >7.8 0.007 >975 11 >16 0.015 >1040 >120.002 >5850 12 14 0.058 241 7 0.058 121 13 <8 0.04 <200 <16 0.03 <533131 >28 0.02 >1555 132 47 0.006 7833 2.3 0.003 767 134 94 0.009 10444 80.0047 1617 135 47 0.0052 9039 3 0.011 273In Vivo Action:MCMV Lethality Test:Animals:

2–3-week old female immunocompetent mice (12–14 g), strain Balb/C AnN orCD1, were purchased from commercial breeders (Bomholtgaard, Iffa,Credo). The animals were not kept under sterile conditions.

Virus Cultivation:

Murine cytomegalovirus (MCMV), Smith strain, was passaged repeatedly invivo in female CD1 mice. 21 days after intraperitoneal infection (2×10⁴plaque forming units/0.2 ml/mouse), the salivary glands were removed,taken up in three times the volume of Minimal Essential Medium (MEM)+10%foetal calf serum (FCS) and homogenized using an Ultraturrax. 10% DMSOv/v were added, 1 ml aliquots were prepared and the virus suspension wasstored at −140° C. Following serial dilution of the salivary glandisolate in steps of ten, the titre was determined in cell culture forNIH 3T3 cells after staining with Giemsa stain, and the lethal dose wasdetermined in vivo in 2–3 week old Balb/C mice.

Virus Infection of the Test Animals Treatment and Evaluation:

2–3 week old female immunocompetent Balb/C mice (12–14 g) were infectedintraperitoneally with 3×1 PFU/0.2 ml/mouse. Starting 6 hours after theinfection, the mice were treated orally with substance twice a day (8.00and 16.00 hours) for a period of 5 days. The dose was 3, 10, 30 or 90mg/kg of body weight, and the volume administered was 10 ml/kg of bodyweight. The substances were formulated in the form of a 0.5% strengthTylose suspension, with 2% of DMSO. The placebo-treated control animalsdie within a period of 4–8 days after the infections. Evaluation wascarried out by determining the percentage of surviving animals followingtreatment with substance, compared to the placebo-treated control group.

HCMV Xenograft Gelfoam® Model:

Animals:

3–4-week old female immunodeficient mice (16–18 g), Fox Chase SCID orFox Chase SCID-NOD, were purchased from commercial breeders(Bomholtgaard, Jackson). The animals were kept under sterile conditions(including bedding and feed) in isolators.

Virus Cultivation:

Human cytomegalovirus (HCMV) Davis Smith strain, was cultivated in vitroon human embryonal foreskin fibroblasts (NHDF cells). The virus-infectedcells were harvested 5–7 days after infection of the NHDF cells with amultiplicity of infection (M.O.I) of 0.01 and stored in the presence ofMinimal Essential Medium (MEM), 10% foetal calf serum (FCS) with 10%DMSO, at −140° C. Following serial dilution of the virus-infected cellsin steps of ten, the titre was determined on 24-well plates of confluentNHDF cells, after vital staining with Neutral Red.

Preparation of the Sponges, Transplantation, Treatment and Evaluation:

Collagen sponges (dimensions 1×1×1 cm, Gelfoam®; from Peasel & Lorey,order No. 407534; K. T. Chong et al., Abstracts of 39^(th) InterscienceConference on Anti-microbial Agents and Chemotherapy, 1999, p. 439) areinitially wetted with phosphate-buffered saline (PBS) and the enclosedair bubbles are removed by degassing, and the sponges are then stored inMEM+10% FCS. 3 hours after the infection, 1×10⁶ virus-infected NHDFcells (infection with HCMV-Davis M.O.I=0.01) are detached and, in 20 μlMEM, 10% FCS, added dropwise to a moist sponge. 12–13 hours later, theinfected sponges are incubated with 5 ng/μl of basic Fibroblast GrowthFactor (bFGF) in 25 μl of PBS/0.1% BSA/1 mM DTT. For transplantation,the immunodeficient mice are anesthetized with Avertin, the fur on theback is removed using an electric shaver, the epidermis is opened 1–2 cmand relieved and the moist sponges are transplanted under the skin ofthe back. The wound caused by the surgery is closed using tissue glue.24 hours after the transplantation, the mice were treated orally withsubstance twice daily (8.00 and 16.00 hours) over a period of 8 days.The dose was 10 or 30 mg/kg of body weight, the administration volumewas 10 ml/kg of body weight. The substances were formulated in the formof a 0.5% strength Tylose suspension with 2% of DMSO. 10 days after thetransplantation and 16 hours after the last administration of substance,the animals were painlessly sacrificed and the sponge was removed. Thevirus-infected cells were released from the sponge by digestion withcollagenase (330 U/1.5 ml) and stored in the presence of MEM, 10% foetalcalf serum, 10% DMSO at −140° C. Following serial dilution of thevirus-infected cells in steps of ten, evaluation was carried out bytitre determination on 24-well plates of confluent NHDF cells, aftervital staining with Neutral Red. What was determined was the number ofinfectious virus particles after treatment with substance, compared tothe placebo-treated control group.

The test described below is used to examine the substances according tothe invention for potential side-effects with respect to an induction ofcytochrome P450 enzymes.

Examination of the Induction of Cytochrome P450 Enzymes in Human LiverCell Cultures:

At a cell density of 2.5×10⁵ cells, primary human hepatocytes werecultivated between two layers of collagen in 24-well microtitre plates,at 37° C. and 5% CO₂, for 8 days. The cell culture medium was changeddaily.

After 48 hours in culture, the hepatocytes were treated for 5 days withdifferent concentrations of the test substances, compared to theinductors rifampicin (50 μM) and phenobarbital (2 mM), each test beingcarried out twice. The final concentrations of the test substances were0.1–10 μg/ml.

Using the cell cultures, the inductive effect of the test substances onthe cytochrome (CYP) P450 enzymes 1A2, 2B6, 2C19 and 3A4 was determinedon day 8 by addition of the substrates 7-ethoxyresorufin (CYP1A2),[¹⁴C]S-mephenytoin (CYP2B6 and 2C19) and [¹⁴C]testosterone (CYP3A4). Theinductive potential of the test substances was determined using themeasured enzyme activities CYP1A2, 2B6, 2C19 and 3A4 of treated cellscompared to untreated cells.

The novel active compounds can be converted in a known manner into thecustomary formulations, such as tablets including coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis case, the therapeutically active compound should in each case bepresent in a concentration from approximately 0.5 to 90% by weight ofthe total mixture, i.e. in amounts which are sufficient in order toachieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifying agents and/or dispersing agents, it being possible, forexample if the diluent used is water, to use organic solvents asauxiliary solvents, if appropriate.

Administrations carried out in a customary manner, preferably orally,parenterally or topically, in particular perlingually or intravenously.

In the case of parenteral administration, solutions of the activecompounds using suitable liquid carrier materials can be employed.

In general, it has been found to be advantageous in the case ofintravenous administration to administer amounts of from about 0.001 to10 mg/kg, preferably from about 0.01 to 5 mg/kg, of body weight toachieve effective results, and in the case of oral administration thedose is about 0.01 to 25 mg/kg, preferably from 0.1 to 10 mg/kg, of bodyweight.

In spite of this, it may be necessary, if appropriate, to depart fromthe amounts mentioned, namely depending on the body weight or on thetype of administration route, on the individual response towards themedicament, the manner of its formulation and the time or interval atwhich administration takes place. Thus, in some cases it may be adequateto manage with less than the above-mentioned minimum amount, while inother cases the upper limit mentioned must be exceeded. In the case ofthe administration of relatively large amounts, it may be advisable todivide these into several individual administrations over the course ofthe day.

Abbreviations:

-   Aloc-Cl allyl chloroformate-   DCM dichloromethane-   DIC N,N′-diisopropylcarbodiimide-   DIEA diisopropylethylamine-   DMF dimethylformamide-   eq. equivalent(s)-   sat. saturated-   HOAc acetic acid-   HOBt hydroxybenzotriazole-   HONSu N-hydroxysuccinimide-   MTP microtitre plate-   PS- polystyrene-resin--   PyBOP benzotriazolyl-N-oxi-tris(dimethylamino)phosphonium    hexafluorophosphate-   Rt retention time-   RT room temperature-   TBABH tetrabutylammonium borohydride-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMOF trimethyl orthoformate    General Procedure for the Reaction of Compounds of the Formula [A-1]    with Compounds of the Formula [A-2] (GP 1):

1.0 eq. of [A-1] are dissolved in dioxane (0.2 M solution), 2.5 eq. ofpyridine are added, the solution is cooled to 5° C. and 1.1 eq. of[A-2], in which Q is preferably chlorine, are added dropwise as a 1.0 Msolution. The mixture is stirred at 5° C. for another 30 min and coolingis then removed, and the mixture is stirred at room temperature for 16h. The mixture is poured into H₂O and the precipitated product isfiltered off with suction, washed with H₂O and dried under high vacuum.

General Procedure for the Hydrogenation of Compounds of the Formula[A-3] (GP 2):

0.14 mol of the compounds [A-3] is dissolved in 500 ml of DMF or ethanoland, under argon, a suspension of 6.0 g of 10% of Pd—C is added. Themixture is then hydrogenated at a hydrogen pressure of 3 bar. After thereaction has gone to completion (monitored by TLC or HPLC), the Pd—Ccatalyst is filtered off and the solvent is removed under reducedpressure. The crude products of the general formula [B-1] are reactedfurther without further purification.

General Procedure for the Sulphonylation of the Compounds of the GeneralFormula [B-1] (GP 3):

Under argon, 1.0 eq. of the compounds [B-1] is dissolved in dioxane (0.2M solution), and 2.5 eq. of pyridine are added. The mixture is stirredat room temperature for 30 min, and 1.1 eq. of the compounds of thegeneral formula [C-1], in which Z is preferably chlorine, dissolved indioxane (1.0 M solution) are then added and the mixture is stirred atroom temperature for 16 h. The solution is then poured into H₂O andextracted 3 times with DCM. The organic phase is washed with sat. NaHCO₃solution, dried over Na₂SO₄ and filtered, and the solvent is removedunder reduced pressure. The residue [C-2] is dried under high vacuum andthen reacted further without further purification.

General Procedure for the Synthesis of Compounds of the General Formula[D-1] from Compounds of the General Formula [C-2] (GP 4):

The compounds of the formula [C-2] (1.0 eq.) are dissolved in ethanol(0.1 M solution), hydroxylamine hydrochloride (1.5 eq.) andtriethylamine (1.6 eq.) are added to the solution and the solution isthen heated under reflux for 4 h and stirred at room temperature foranother 16 h. The solvent is removed under reduced pressure, the residueis taken up in ethyl acetate and extracted 3× with water, the organicphase is dried over MgSO₄ and filtered and the solvent is removed underreduced pressure. The residue [D-1] is dried under high vacuum.

General Procedure for the Reaction of the Compounds of the GeneralFormula [D-1] with Compounds [E-1] (GP 5):

1.0 eq. of the compounds of the general formula [D-1], 1.05 eq. ofcarboxylic acid [E-1] and 1.1 eq. of PyBOP are initially charged in THF(0.1 M solution), 1.1 eq. of N,N-diisopropylethylamine are added to thesuspension and the resulting solution is stirred at room temperature for16 h. The mixture is then diluted with 10 ml of DCM and extracted ineach case once with 1 N HCl, sat. NaHCO₃ solution and sat. NaClsolution. The organic phase is dried over Na₂SO₄ and filtered and thesolvent is removed under reduced pressure. The crude product is directlyreacted further.

General Procedure for the Synthesis of a 1,2,4-Oxadiazole from the CrudeProduct Obtained According to GP 5 (GP 6):

1.0 mmol of crude product, obtained according to GP 5, is taken up in 10ml of DMF, and the solution is heated at 110° C. Once the reaction hasgone to completion (monitored by TLC or HPLC, about 2–16 h), the mixtureis diluted with DCM and extracted twice with H₂O. The combined aqueousphases are extracted twice with DCM, the organic phases are combined,dried over Na₂SO₄ and filtered and the solvent is removed under reducedpressure. The resulting compounds of the general formula (I) arepurified by silica gel chromatography (cyclohexane/ethyl acetate) or bypreparative HPLC.

General Procedures for Syntheses Using Polymeric Supports:

General Procedure for the Synthesis of 1,3,4-Oxadiazoles According toScheme 4:

The reactions according to Scheme 4 were carried out on a polymericsupport using the IRORI system according to the “Split & Mix” method,known to the solid-phase chemist, employing 4 carbonyl chlorides, 24carboxylic acids and the two meta- or para-isomers of thephenylenediamine or sulphonyl chloride. Here, the first two steps werecarried out in a flask, the other steps in IRORI MiniKans (100 mg ofresin per can).

Synthesis of the Starting Resins (I) and (II) for the Syntheses on thePolymeric Support According to Scheme 4:

Reductive Amination of Formyl Resin (from Nova Biochem, 0.78 mmol/g):

The formyl resin (1.0 eq.) is, in a flask, suspended in TMOF/DMF (100 mlper 12.5 g of resin), and the diamine (6.0 eq.) is added. The suspensionis shaken at 40° C. for 16 h, and a freshly prepared solution of TBABH(4.0 eq.) and HOAc (16.0 eq.) in DMF is then added. After 8 h at RT, thesolvent is filtered off, and once more, reduction solution is added tothe resin. After a further 16 h at RT, the solvent is filtered off withsuction and the resin (I) is washed in each case 2× with in each case200 ml of 50% strength HOAc, DMT, THF and DCM and dried under highvacuum.

Sulphonylation of Polymer-Bound Phenylenediamine:

The resin (I) (1.0 eq.) is taken up in THF, and the sulphonyl chloride(1.5 eq.) is added. The suspension is shaken at RT for 16 h, and thesolvent is filtered off with suction. The resin (H) is then washed ineach case 2× with in each case 100 ml of 50% strength HOAc, DMF, THF andDCM and dried under high vacuum.

Preparation of the Resin for the IRORI System:

The resins of type II are distributed as a suspension (per 3.0 g ofresin: 30 ml of DMF/DCM 2:1 v/v) into in each case 96 MiniKans (1 mlsuspension per Kan) and washed in each case three times with DCM, andthe Kans are dried under reduced pressure.

Reaction Sequence (IRORI):

Acylation with Acid Chlorides:

The Kans are sorted and taken up in THF, 5.0 eq. of DIEA and 5.0 eq. ofacid chloride are added and the Kans are evacuated briefly and shaken atRT for 3 h. The reaction solutions are then separated off and the Kansare combined and washed (in each case 2×50% strength HOAc, DMF, THF,DCM).

Hydrazide Synthesis:

The combined Kans are taken up in a mixture of 2 N NaOH/MeOH/THF (5:7:15v/v), evacuated briefly and stirred at 50° C. for 5 h. The Kans are thenwashed (in each case 2×50% strength HOAc, DMF, THF, DCM) and dried underreduced pressure.

The Kans are then taken up in THF, 5 eq. of DIC and 10 eq. of HONSu areadded and the Kans are shaken at RT for 3 h. The Kans are filtered off,washed 2× with THF and then once more taken up in THF, and 3 eq. ofhydrazine hydrate are added. After a further 3 h at RT, the Kans arefiltered off with suction and washed in each case 2× with 50% strengthHOAc, DMF, THF and DCM.

Acylation with Carboxylic Acids/DIC/HOBt:

3 eq. of DIC, 6 eq. of DIEA and 6 eq. of HOBt are added to thecarboxylic acids (3 eq.) in THF. After 60 min of activation at RT, thesolution is added to the Kans, which have been sorted beforehand, and isshaken at RT for 16 h. The Kans are then combined, washed (in each case2× with 50% strength HOAc, DoF, THF, DCM) and dried under reducedpressure.

Cyclization to the 1,3,4-oxadiazole:

The combined Kans are taken up in DMF, DCI (10 eq.) is added and theKans are evacuated briefly and stirred at 110° C. for 48 h. The Kans arethen washed (in each case 2× with 50% strength HOAc, DMF, THF, DCM) anddried under reduced pressure.

Cleavage from the Polymeric Support:

After sorting into IRORI cleavage blocks, the Kans are cut open, theresin is distributed into FlexChem blocks and the products are cleavedin a Deep-Well MTP using in each case 1.0 ml of TFA/DCM (1:1 v/v) at RTfor 45 min. The resin is washed with DCM and the solvent is evaporated.

General Procedure for the Synthesis of the 1,3,4-thiadiazoles Accordingto Scheme 5:

The synthesis is carried out by a mixed approach of solid-phasesynthesis and synthesis in solution.

Synthesis of the Monosulphonylated Phenylenediamine:

The phenylenediamine (1.0 eq.) is dissolved in TBF (0.4 M solution), 1.0eq. of sulphonyl chloride are added and the mixture is stirred at RT for16 h. The mixture is then diluted with DCM and extracted 2× with water,the aqueous phases are reextracted 1× with DCM and the org. phases arecombined, dried over Na₂SO₄ and concentrated using a rotary evaporator.The crude product is reacted further without further purification.

Attachment to the Polymeric Support and Synthesis of the Thiadiazole:

Reductive Amination of Formyl Resin (from Nova Biochem, 0.78 mmol./g):

The formyl resin (1.0 eq.) is, in a flask, suspended in TMOF/DMF (100 mlper 12.5 g of resin), and the sulphonylated phenylenediamine (6.0 eq.)is added. The suspension is shaken at 40° C. for 16 h, and a freshlyprepared solution of TBABH (4.0 eq.) and HOAc (16.0 eq.) in DMF is thenadded. After 8 h at RT, the solvent is filtered off, and once more,reduction solution is added to the resin. After a further 16 h at RT,the solvent is filtered off with suction and the resin is washed in eachcase 2× with in each case 200 ml of 50% strength HOAc, DMF, THF and DCMand dried under high vacuum.

Acylation of the Resin:

In a syringe with PE fritt (from MultiSyntech), the resin is suspendedin THF, and 3.0 eq. of DIEA and 3.0 eq. of carbonyl chloride are added.The suspension is shaken at RT for 3 h and then filtered off withsuction, and the resin is washed in each case 2× with 50% strength HOAc,DMF, THF and DCM.

Hydrazide Synthesis:

In a syringe with PE fritt (from MultiSyntech), the resin is taken up ina mixture of 2 N NaOH/MeOH/THF (5:7:15 v/v), stirred at 50° C. for 5 hand then washed (in each case 2× with 50% strength HOAc, DMF, THF, DCM).The resin is then taken up in THF, 5 eq. of DIC and 10 eq. of HONSu areadded and the mixture is shaken at RT for 3 h. The resin is filteredoff, washed 2× with THF and then once more taken up in THF, and 3 eq. ofhydrazine hydrate are added. After a further 3 h at RT, the resin isfiltered off with suction and washed (in each case 2× with 50% strengthHOAc, DMF, THF, DCM).

Acylation of the Hydrazide with Carboxylic Acids/DIC/HOBt:

3 eq. of DIC, 6 eq. of DIEA and 6 eq. of HOBt are added to thecarboxylic acid (3 eq.) in THF. After 6 min of activation at roomtemperature, the solution is added to the resin (1 ml per 100 mg ofresin), and the mixture is shaken at RT for 16 h. The resin is thenfiltered off with suction and washed (in each case 2× with 50% strengthHOAc, DMF, THF, DCM). The LC-MS of the cleaved sample shows that thedouble bond of the allyloxycarbonyl group is hydrogenated in thisreaction.

Thiadiazole Synthesis:

The resin is initially charged in dioxane (1 ml per 100 mg of resin),5.0 eq. of Lawesson's reagent are added and the mixture is stirred at90° C. for 3 h. The resin is then filtered off with suction and washedin each case 2× with DMF, 50% strength HOAc, DMF, THF and DCM.

Cleavage from the Polymeric Support, Removal of the Carbonate ProtectiveGroup and Synthesis of the Amide:

The resin is treated with TFA/DCM (1:1 v/v, 1 ml per 100 mg of resin)and, after 45 min, filtered off and washed with DCM (same volume). TFAand DCM are removed under reduced pressure and the residue is taken upin ethanol/2.5 N NaOH (1:1 v/v, 0.5 M solution), stirred at 75° C. for16 h, diluted with DCM and extracted 2× with water, the aqueous phase isadjusted to pH 7 using 1 N HCl and extracted 3× with DCM, all org.phases are combined, washed 2× with water, dried over Na₂SO₄ andconcentrated using a rotary evaporator. The residue is taken up in THF,1.05 eq. of DEA and 1.05 eq. of acid chloride are added and the mixtureis shaken at RT for 16 h. Volatile components are then removed underreduced pressure and the product is isolated by preparative HPLC.

Starting Materials:

EXAMPLE I 1-Methyl-N-(3-nitrophenyl)-cyclopropanamide

This compound is prepared according to GP 1 from 80.0 g of3-nitroaniline.

Yield: 107 g (81% of theory)

EXAMPLE II 3-Fluor-2,2-dimethyl-N-(3-aminophenyl)-propanamide

This compound is prepared according to GP 1 and GP 2 from3-nitroaniline, without purification of the intermediate.

Yield: 85% of theory (over 2 steps)

EXAMPLE III 1-Methyl-N-(3-aminophenyl)-cyclopropanamide

This compound is prepared according to GP 2 from 107 g of the compoundfrom Example 1.

Yield: 80 g (87% of theory)

EXAMPLE IV3-Fluoro-2,2-dimethyl-N-(3-{[(4-methylphenyl)sulphonyl]amino}phenyl)-propanamide

This compound is prepared according to GP 3 from 18.68 g of the compoundfrom Example II.

Yield: 19.96 g (78% of theory)

EXAMPLE VN-{3-[({4-[Amino(hydroxyimino)methyl]phenyl}sulphonyl)amino]phenyl}-3-fluoro-2,2-dimethylpropanamide

This compound is prepared according to GP 4 from 10.0 g of the compoundfrom Example IV.

Yield: 10.5 g (97% of theory)

EXAMPLE VIN-(3-{[(4-Cyanophenyl)sulphonyl]amino}phenyl)-1-methylcyclopropanecarboxamide

This compound is prepared according to GP 3 from 90 g of the compoundfrom Example III.

Yield: 150 g of crude product (quant.) HPLC: Rt=2.87 min (HPLCmethod/instrument 9)

EXAMPLE VIIN-{3-[({4-[Amino(hydroxyimino)methyl]phenyl}sulphonyl)amino]phenyl}-1-methyl-cyclopropanecarboxamide

This compound is prepared according to GP 3 from 168 g of the compoundfrom Example VI (as crude product).

Yield: 118 g (57% of theory) HPLC: Rt=2.7 min (HPLC method/instrument 5)MW 388.45; m/z found: 389.

EXAMPLE VIII 2-Aminoacetyl-picoline

25.0 g (0.23 mol) of 6-aminopicoline are dissolved in 250 ml of aceticacid, and 47.2 g (0.46 mol) of acetic anhydride are added with stirringand ice-cooling. Initially, the mixture is stirred with ice-cooling foranother 30 min, and the ice bath is then removed and stirring iscontinued at room temperature for 16 h. The clear solution is thenconcentrated under reduced pressure. The oily residue is crystallized inan ice bath and the crystals are dried under reduced pressure.

Yield: 28 g (80.6% of theory) ¹H-NMR (200 MHz, DMSO-d₆): δ=10.41 (s,1H), 7.87 (d, 1H), 7.63 (t, 1H), 6.93 (d, 1H), 2.39 (s, 3H), 2.06 (s,3H).

EXAMPLE IX 2-Aminoacetyl-picolinic acid

31.0 g (0.21 mol) of 2-aminoacetylpicoline are dissolved in 310 ml ofwater and heated at 75° C., and 60.0 g (0.38 mol) of potassiumpermanganate are added a little a time over a period of 3 h such thatthe violet colour disappears again in each case. The mixture is stirredat 75° C. for another 5 h, and the hot reaction mixture is thenfiltered. The aqueous phase is extracted four times with dichloromethaneand then acidified to pH 4 using 1 N hydrochloric acid. The precipitateis filtered off, washed with 0.1 N hydrochloric acid and dried underreduced pressure.

Yield: 15.5 g (42% of theory) HPLC: Rt=1.11 min (HPLC method/instrument3) MW 180.16; m/z found: 181 ¹H-NMR (200 MHz, DMSO-d₆): δ=13.23 (br s,1H), 10.81 (s, 1H), 8.28 (d, 1H), 7.94 (t, 1H), 7.73 (dd, 1H), 2.12 (s,3H).

WORKING EXAMPLES

The 1,2,4-oxadiazoles attached in the 3-position shown in the workingexamples below were prepared from compounds of type Example V accordingto GP 5 and GP 6.

Example 13-Fluoro-2,2-dimethyl-N-{3-[({4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}propanamide

5.93 g (45.92 mmol) of N,N-diisopropylethylamine, 5.65 g (45.92 mmol) ofpicolinic acid and 23.89 g (45.92 mmol) of PyBOP are initially chargedin 70 ml of THF, the mixture is stirred at room temperature for 30 min,17.05 g (41.74 mmol) of amidoxime from Example V are then added and thesolution is stirred at room temperature for 16 h. The reaction mixtureis concentrated under reduced pressure, the residue is taken up in 50 mlof DMF and the solution is stirred at 110° C. for 4 h. The mixture isthen diluted with 300 ml of DCM, and the organic phase is extractedthree times with in each case 200 ml of 2 N H₂SO₄ and once with sat.NaHCO₃ solution. The organic phase is dried over Na₂SO₄ and filtered,and the solvent is removed under reduced pressure (43.5 g of crudeproduct). The product is purified by silica gel chromatography usingcyclohexane/ethyl acetate (6:4 v/v) and, after purification, stirredwith cyclohexane, and the solid is filtered off with suction and driedunder reduced pressure.

Yield: 12.59 g (61% of theory) of a white solid m.p.: 178.9° C. MW495.53; m/z found: 496 HPLC Rt: 4.38 min. (LC method/instrument 3)¹H-NMR (300 MHz, DMSO): δ=1.20 (s, 3 H), 1.21 (s, 3 H), 4.48 (d, 2 H),6.81 (d, 1 H), 7.14 (t, 1 H), 7.31 (d, 1 H), 7.58 (s, 1 H), 7.71–7.78(m, 1 H), 7.99 (d, 2 H), 8.09–8.18 (m, 1 H), 8.27 (d, 2 H), 8.34 (d, 1H), 8.86 (d, 1 H), 9.35 (s, 1 H), 10.43 (s, 1 H).

Example 2N-(3-{[(4-{5-[3-(Dimethylamino)phenyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]-amino}phenyl)-1-methylcyclopropanecarboxamide

MW 517.61; m/z found: 518 HPLC Rt: 3.25 min. (HPLC method/instrument: 3)¹H-NMR (300 MHz, DMSO): δ=0.54–0.64 (m, 2 H), 1.00–1.09 (m, 2 H), 1.36(s, 3 H), 3.00 (s, 6 H), 6.79 (d, 1 H), 7.02–7.50 (m, 6 H), 7.57 (t, 1H), 7.97 (d, 2 H), 8.24 (d, 2 H), 9.15 (s, 1 H), 10.34 (s, 1 H).

Example 31-Methyl-N-{3-[({4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)-amino]phenyl}cyclopropanecarboxamide

20.0 g (51.59 mmol) of the appropriate amidoxime, 6.66 g (54.06 mmol) ofpicolinic acid and 29.47 g (56.66 mmol) of PyBOP are initially chargedin 60 ml of THF, 7.32 g (56.66 mmol) of N,N-diisopropylethylamine areadded at room temperature to the suspension and the resulting clearsolution is stirred at room temperature for 16 h. The mixture is thendiluted with 250 ml of DCM and extracted in each case once with in eachcase 250 ml of 1 N HCl, sat. NaHCO₃ solution and sat. NaCl solution. Theorganic phase is dried over Na₂SO₄ and filtered, and the solvent isremoved under reduced pressure. The crude product (25.41 g) is taken upin 250 ml of DMF, and the solution is stirred at 110° C. for 2.5 h. Themixture is then diluted with 250 ml of DCM, and the organic phase isextracted twice with in each case 250 ml of H₂O. The combined aqueousphases are extracted twice with in each case 250 ml of DCM, the organicphases are combined, dried over Na₂SO₄ and filtered and the solvent isremoved under reduced pressure (43.5 g of crude product). The product ispurified by chromatography on silica gel 60 using cyclohexane/ethylacetate 1:1 v/v.

Yield: 18.35 g (75% of theory) of a white solid m.p.: 202° C. MW 475.53;m/z found: 476 HPLC Rt: 4.0 min. (HPLC method/instrument: 6) ¹H-NMR (200Mz, DMSO): δ=0.55–0.64 (m, 2 H), 1.00–1.10 (m, 2 H), 1.36 (s, 3 H), 6.78(d, 1 H), 7.11 (t, 1 H), 7.27 (d, 1 H), 7.57 (s, 1 H), 7.70–7.79 (m, 1H), 8.08 (d, 2 H), 8.09–8.19 (m, 1 H), 8.26 (d, 2 H), 8.34 (d, 1 H),8.87 (d, 1 H), 9.17 (s, 1 H), 10.38 (s, 1 H).

Example 4N-{3-[({4-[5-(2-Amino-1,3-thiazol-4-yl)-1,2,4-oxadiazol-3-yl])phenyl}sulphonyl)-amino]phenyl}-1-methylcyclopropanecarboxamide

MW 496.57; m/z found: 497 HPLC Rt: 2.508 min. (HPLC method/instrument:8) ¹H-NMR (200 MHz, DMSO): δ=0.54–0.64 (m, 2 H), 1.00–1.09 (m, 2 H),1.36 (s, 3 H), 6.78 (d, 1 H), 7.12 (t, 1 H), 7.28 (d, 1 H), 7.52 (s, 1H), 7.57 (s, 1 H), 7.82 (s, 1 H), 7.95 (d, 2 H), 8.19 (d, 2 H), 9.18 (s,1 H), 10.38 (s, 1 H).

Example 51-Methyl-N-{3-[({4-[5-(6-methyl-2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}cyclopropanecarboxamide

MW 489.55; m/z found: 490 HPLC Rt: 4.76 min. (HPLC method/instrument: 6)¹H-NMR (200 MHz, DMSO): δ=0.54–0.63 (m, 2 H), 1.00–1.09 (m, 2 H), 1.36(s, 3 H), 2.61 (s, 3 H), 6.77 (d, 1 H), 7.10 (t, 1 H), 7.26 (d, 1 H),7.50–7.65 (m, 2 H), 7.92–8.06 (m, 3 H), 8.14 (d, 1 H), 8.25 (d, 2 H),9.17 (s, 1 H), 10.39 (s, 1 H).

Example 61-Methyl-N-{3-[({4-[5-(3-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}cyclopropanecarboxamide

MW 478.53; m/z found: 479 HPLC Rt: 3.77 min. (HPLC method/instrument: 6)¹H-NMR (200 MHz, DMSO): δ=0.54–0.65 (m, 2 H), 0.99–1.12 (m, 2 H), 1.36(s, 3 H), 2.34 (s, 3 H), 6.77 (d, 1 H), 7.10 (t, 1 H), 7.25 (d, 1 H),7.54 (s, 1 H), 7.95 (d, 2 H), 8.20 (d, 2 H), 9.16 (s, 1 H), 10.38 (s, 1H), 13.58 (s, 1 H).

Example 71-Methyl-N-{3-[({4-[5-(1,3-thiazol-4-yl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)-amino]phenyl}cyclopropanecarboxamide

MW 481.56; m/z found: 482 HPLC Rt: 2.689 min. (HPLC method/instrument:8) ¹H-NMR (300 Mz, DMSO): δ=0.55–0.63 (m, 2 H), 1.01–1.09 (m, 2 H), 1.36(s, 3 H), 6.77 (d, 1 H), 7.12 (t, 1 H), 7.28 (d, 1 H), 7.58 (s, 1 H),7.98 (d, 2 H), 8.24 (d, 2 H), 8.95 (d, 1 H), 9.19 (s, 1 H), 9.40 (d, 1H), 10.39 (s, 1 H).

Example 8N-{3-[({4-[5-(1,5-Dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}-1-methylcyclopropanecarboxamide

MW 492.56; m/z found: 493 HPLC Rt: 2.788 min. (HPLC method/instrument:8) ¹H-NMR (200 MHz, DMSO): δ=0.53–0.64 (m, 2 H), 0.97–1.12 (m, 2 H),1.36 (s, 3 H), 2.35 (s, 3 H), 3.89 (s, 3 H), 6.77 (d, 1 H), 6.85 (s, 1H), 7.11 (t, 1 H), 7.27 (d, 1 H), 7.56 (s, 1 H), 7.95 (d, 2 H), 8.21 (d,2 H), 9.18 (s, 1 H), 10.38 (s, 1 H).

Example 91-Methyl-N-{3-[({4-[5-(5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}cyclopropanecarboxamide

MW 478.53; m/z found: 479 HPLC Rt: 2.614 min. (HPLC method/instrument:8) ¹H-NMR (300 MHz, DMSO): δ=0.57–0.63 (m, 2 H), 1.01–1.08 (m, 2 H),1.36 (s, 3 H), 2.34 (s, 3 H), 6.75–6.80 (m, 2 H), 7.10 (t, 1 H), 7.26(d, 1 H), 7.54 (s, 1 H), 7.96 (d, 2 H), 8.20 (d, 2 H), 9.16 (s, 1 H),10.38 (s, 1 H), 13.58 (s, 1 H).

Example 10N-{3-[({4-[5-(1-Isoquinolinyl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)-amino]phenyl}-1-methylcyclopropanecarboxamide

MW 525.59; m/z found: 526 HPLC Rt: 4.34 min. (HPLC method/instrument: 5)¹H-NMR (200 MHz, DMSO): δ=0.54–0.67 (m, 2 H), 0.99–1.11 (m, 2 H), 1.36(s, 3 H), 6.80 (d, 1 H), 7.12 (t, 1 H), 7.28 (d, 1 H), 7.58 (s, 1 H),7.86–7.99 (m, 2 H), 8.01 (d, 2 H), 8.15–8.29 (m, 1 H), 8.26 (d, 1 H),8.36 (d, 2 H), 8.82 (d, 1 H), 9.18 (s, 1 H), 9.26–9.36 (m, 1 H), 10.41(s, 1 H).

Example 111-Methyl-N-{3-[({4-[5-(2-methyl-1,3-thiazol-4-yl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}cyclopropanecarboxamide

MW 495.58; m/z found: 496 HPLC Rt: 2.813 min. (HPLC method/instrument:8) ¹H-NMR (200 MHz, DMSO): δ=0.55–0.63 (m, 2 H), 1.00–1.09 (m, 2 H),1.36 (s, 3 H), 2.78 (s, 3 H), 6.78 (d, 1 H), 7.12 (t, 1 H), 7.28 (d, 1H), 7.58 (s, 1 H), 7.97 (d, 2 H), 8.23 (d, 2 H), 8.73 (s, 1 H), 9.19 (s,1 H), 13.39 (s, 1 H).

Example 12N-(3-{[(4-{5-[2-(Aminomethyl)-1,3-thiazol-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)-sulphonyl]amino}phenyl)-1-methylcyclopropanecarboxamide

MW 510.60, m/z found: 511 HPLC Rt: 1.71 min. (HPLC method/instrument: 8)¹H-NMR (200 MHz, DMSO): δ=0.54–0.64 (m, 2 H), 0.99–1.09 (m, 2 H), 1.36(s, 3 H), 4.09 (s, 2 H), 6.77 (d, 1 H), 7.11 (t, 1 H), 7.27 (d, 1 H),7.56 (s, 1 H), 7.96 (d, 2 H), 8.22 (d, 2 H), 8.75 (s, 1 H), 9.18 (s, 1H).

Example 133-Fluoro-2,2-dimethyl-N-[4-({[3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl]sulphonyl}-amino)phenyl]propanamide

MW 494.54; m/z found: 495 HPLC Rt: 4.8 min. (HPLC method/instrument: 3)¹H-NMR (300 MHz, DMSO): δ=1.17 (s, 6 H), 4.44 (d, 2 H), 7.04 (d, 2 H),7.48 (d, 2 H), 7.63–7.81 (m, 4 H), 7.90 (d, 1 H), 8.22 (d, 2 H), 8.30(d, 1 H), 8.45 (s, 1 H), 10.31 (s, 1 H).

Further 1,2,4-oxadiazole derivatives which are attached via position 3and were prepared in accordance with the processes according to theinvention are listed in Table 2:

Ex- am- HPLC HPLC m/z ple R₁ method/ found No. Structure MW [min]instrument [M + H] 14

525.59 5.03 6 526 15

476.51 2.63 8 477 16

517.61 4.28 3 518 17

475.53 3.90 6 476 18

554.42 4.80 3 554(79Br) 19

521.60 3.14 8 522 20

495.53 4.34 3 496 21

491.53 3.40 6 492 22

495.53 4.13 3 496 23

494.54 4.95 3 495 24

482.54 2.72 8 483 25

463.52 2.83 8 464 26

501.56 4.41 3 502 27

501.56 4.96 3 502 28

475.53 2.66 8 476 29

475.53 2.70 8 476 30

492.00 4.46 3 493 31

495.53 4.44 3 496 32

554.42 4.75 3 555 33

475.53 3.89 6 476 34

496.57 3.65 5 497 35

496.52 4.30 3 497 36

496.52 4.33 3 497 37

529.58 2.68 8 530 38

464.50 2.36 8 465 39

496.57 2.52 8 497 40

516.58 4.19 3 517 41

496.57 3.59 5 497 42

509.54 2.69 8 510 43

491.53 3.98 3 492 44

474.54 4.55 6 475 45

495.53 4.17 3 496 46

495.53 4.49 3 496 47

475.52 2.63 8 476 48

494.54 4.87 3 495 49

492.00 4.10 3 493 50

495.53 4.18 3 496 51

496.52 4.32 3 497 52

496.52 4.35 3 497 53

475.52 2.60 8 476 54

555.61 4.64 6 556

Further 1,3,4-oxadiazole derivatives attached via position 5 andprepared according to the processes according to the invention arelisted in Table 3:

Exam- ple m/z found HPLC R₁ HPLC method/ No. Structure MW [M + H] [min]instrument 55

494.55 495 4.15 6 56

517.61 515 4.26 6 57

474.54 475 4.17 6 58

517.61 518 4.35 6 59

537.62 538 4.3 6 60

511.00 511, 513 (35Cl,37Cl) 4.31 6 61

476.58 477 4.23 6 62

519.63 520 4.38 6 63

519.63 520 4.44 6 64

517.61 518 4.33 6 65

475.53 476 3.66 6 66

554.07 554, 556 (35Cl,37Cl) 4.48 6 67

494.55 495 4.20 6 68

537.62 538 4.37 6 69

476.56 477 4.27 6 70

474.54 475 4.17 6 71

475.53 476 3.60 6 72

537.62 538 4.35 6 73

475.53 475 3.69 6 74

475.53 476 3.54 6 75

554.07 554, 556 (35Cl,37Cl) 4.47 6 76

474.54 475 4.13 6 77

519.63 520 4.43 6 78

511.99 512, 514 (35Cl,37Cl) 3.84 6 79

494.55 495 4.2 6 80

476.56 477 4.28 6 81

475.53 476 3.6 6 82

511.00 511, 513 (35Cl,37Cl) 4.32 8 83

517.61 518 4.29 6 84

477.55 478 3.77 6 85

476.52 477 3.56 6 86

495.54 496 3.71 6 87

475.53 476 3.55 6 88

511.99 512, 514 (35Cl,37Cl) 3.78 6 89

475.53 476 3.55 6 90

537.62 538 4.32 6 91

476.52 477 3.57 6 92

494.55 495 4.17 6 93

495.54 496 3.6 6 94

495.54 496 3.64 6 95

477.55 478 3.71 6 96

476.56 477 4.24 6 97

476.52 477 3.51 6 98

511.99 512, 514 (35Cl,37Cl) 3.78 6 99

475.53 476 3.48 6 100

477.55 478 3.8 6 101

511.99 512, 514 (35Cl,37Cl) 3.87 6 102

495.54 496 3.54 6 103

495.54 496 3.64 6 104

519.63 520 4.4 6 105

475.53 476 3.55 6 106

477.55 478 3.71 6 107

477.55 478 3.67 6 108

478.53 479 3.67 6 109

512.98 513, 515 (35Cl,37Cl) 3.76 6 110

496.52 497 3.60 6 111

511.99 512, 514 (35Cl,37Cl) 3.73 6 112

495.54 496 3.73 6 113

495.54 496 3.6 6 114

495.52 497 3.57 6 115

477.55 478 3.61 6 116

511.99 512, 514 (35Cl,37Cl) 3.74 6 117

495.54 496 3.59 6 118

478.53 479 3.68 6 119

475.53 476 3.5 6 120

478.53 479 3.64 6 121

477.55 478 3.66 6 122

477.55 478 3.66 6 123

477.55 478 3.67 6 124

495.54 496 3.60 6 125

496.52 497 3.61 6 126

476.52 477 3.51 6 127

511.99 512, 514 (35Cl,37Cl) 3.86 6 128

495.54 496 3.55 6 129

496.52 497 3.56 6 130

477.55 478 3.62 6

Example 1311-Methyl-N-{4-[({3-[5-(2-pyridinyl)-1,3,4-thiadiazol-2-yl]phenyl}sulphonyl)amino]phenyl}cyclopropanecarboxamide

MW 491.59; m/z found: 490 (neg. ESI) HPLC Rt: 4.03 min. (HPLCmethod/instrument: 5) ¹H-NMR (400 MHz, DMSO): δ=0.56–0.59 (m, 2 H),1.01–1.06 (m, 2 H), 1.34 (s, 3 H), 7.04 (d, 2 H), 7.48 (d, 2 H),7.63–7.65 (m, 1 H), 7.76 (t, 3H), 7.88 (d, 1H), 8.09 (dt, 1H), 8.26 (dt,1H), 8.34 (d, 1H), 8.44 (t, 1H), 8.75–8.77 (m, 1H), 10.10 (s, 1 H),10.27 (s, 1 H).

Example 132N-(3-{[(4-{5-[6-(Acetylamino)-2-pyridinyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]-amino}phenyl)-1-methylcyclopropanecarboxamide

8.1 g (20.85 mmol) of amidoxime from Example VII are initially chargedin 50 ml of THF, 4.13 g (22.94 mmol) of 2-aminoacetylpicolinic acid(Example IX) and 16.28 g (31.28 mmol) of PyBOP are then added, and 2.96g (22.94 mmol) of N,N-diisopropylethylamine are then added dropwise. Themixture is stirred at room temperature for 16 h, and the reactionmixture is then concentrated under reduced pressure, taken up indichloromethane and washed successively, in each case once, with 1 Nhydrochloric acid and sat. sodium chloride solution. The organic phaseis dried over sodium sulphate, filtered and concentrated under reducedpressure. The residue (8.26 g) is dissolved in 75 ml ofN,N-dimethylformamide and stirred at 115° C. for 4 h. After cooling, 200ml of ethyl acetate are added and the mixture is washed 1× with 1 Nhydrochloric acid, 1× with sat. sodium chloride solution, 2× with sat.sodium bicarbonate solution and 1× with sat. sodium chloride solution.During washing, crystallization sets in in the organic phase.Accordingly, the organic phase is allowed to stand for 30 min and theprecipitated crystals are filtered off with suction and washed withmethanol [1. fraction, yield: 5.04 g (23% of theory)]. The mother liquoris dried over sodium sulphate, filtered and concentrated using a rotaryevaporator. Stirring with dichloromethane gives two further fractions ofcrystalline product [fraction 2, yield: 3.5 g (16% of theory); fraction3, yield: 1.1 g (5% of theory)]. The remaining mother liquor containsmore product which can be purified chromatographically [yield: 1.01 g(5% of theory)].

HPLC: Rt=4.42 min (HPLC method/instrument 3) MW 550.59; m/z found: 551¹H-NMR (200 MHz, DMSO-d₆): δ=11.00 (s, 1H); 10.41 (s, 1H); 9.18 (s, 1H);8.40 (dd, 1H); 8.24 (d, 2H); 8.14–9.97 (m, 4H); 7.57 (t, 1H); 7.27 (d,1H); 7.12 (t, 1H); 6.78 (d, 1H); 2.15 (s, 3H); 1.37 (s, 3H); 1.08–1.03(m, 2H); 0.62–0.57 (m, 2H).

Example 133N-(3-{[(4-{5-[6-(Acetylamino)-2-pyridinyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]-amino}phenyl)-3-fluoro-2,2-dimethylpropanamide

7.80 g (19.1 mmol) of the amidoxime from Example V are initially chargedin 100 ml of THE, 3.78 g (21.0 mmol) of 2-aminoacetylpicolinic acid and14.91 g (28.6 mmol) of PyBOP are then added, and 2.71 g (21.0 mmol) ofN,N-diisopropylethylamine are finally added dropwise. The mixture isstirred at 40° C. for 16 h and the reaction mixture is then concentratedunder reduced pressure, taken up in ethyl acetate and washedsuccessively, in each case twice, with 1 N hydrochloric acid and sat.sodium chloride solution. The organic phase is dried over sodiumsulphate, filtered and concentrated under reduced pressure. The productis purified by filtration through silica gel 0.60 using the mobile phaseethyl acetate. The resulting product (9.9 g) is dissolved in 90 ml ofN,N-dimethylformamide and stirred at 115° C. for 4 h. After cooling, thesolvent is removed under reduced pressure, 200 ml of ethyl acetate areadded and the mixture is washed 1× with 1 N hydrochloric acid, 1× withsat. sodium chloride solution, 2× with sat. sodium bicarbonate solutionand 1× with sat. sodium chloride solution. The organic phase is driedover sodium sulphate and the solvent is then removed. Duringconcentration, a precipitate is formed, and the suspension is thendiluted with dichloromethane and the precipitate is separated off andwashed with dichloromethane.

Yield: 5.4 g (55% of theory) HPLC: Rt=4.44 min (HPLC method/instrument3) MW 552.58; m/z found: 553 ¹H-NMR (200 MHz, DMSO-d₆): δ=10.99 (s, 1H);10.43 (s, 1H); 9.36 (s, 1H); 8.40 (dd, 1H); 8.25 (d, 2H); 8.13–7.98 (m,4H); 7.59 (t, 1H); 7.30 (d, 1H); 7.15 (t, 1H); 6.81 (d, 1H); 4.48 (d,1H); 2.16 (s, 3H); 1.21 (s, 6H).

Example 134N-{3-[({4-[5-(6-Amino-2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)amino]-phenyl}-1-methylcyclopropanecarboxamide

15 g (28.16 mmol) of the compound from Example 132 are suspended in 370ml of ethanol, and 279 ml (281.7 mmol) of 1 N aqueous sodium hydroxidesolution are added. The mixture is stirred at 45° C. for 5 h (thesuspension dissolves slightly), and the mixture is then, in an ice bath,adjusted to pH=5 using 1 N hydrochloric acid, and the precipitatedcrystals are filtered off, washed with water and ethanol and dried at80° C. under high vacuum for 16 h.

Yield: 12 g (85.5% of theory) HPLC: Rt=4.06 min (HPLC method/instrument3) MW 490.54; m/z found: 491 ¹H-NMR (200 MHz, DMSO-d₆): δ=10.40 (s, 1H);9.15 (s, 1H); 8.21 (d, 2H); 7.96 (d, 2H); 7.68–7.43 (m, 3H); 7.25 (d,1H); 7.10 (t, 1H); 6.76 (t, 2H); 6.56 (d, 2H); 1.36 (s, 3H); 1.08–1.03(s, 2H); 0.62–0.57 (m, 2H).

Example 135N-{3-[({4-[5-(6-Amino-2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)amino]-phenyl}-3-fluoro-2,2-dimethylpropanamide

19.3 g (34.9 mmol) of the compound from Example 133 are taken up in 290ml of a mixture of water/conc. hydrochloric acid (1:1 v/v), and thesuspension is stirred at 100° C. for 4 h. The suspension is thenfiltered, the filter cake is stirred between sat. sodium bicarbonatesolution and ethyl acetate, the organic phase is separated off andconcentrated using a rotary evaporator and the crude product is purifiedchromatographically [silica gel 60, mobile phase toluene/acetone (8:2v/v)]. To remove adhering residual solvent, the clean fractions arecombined (6.8 g), dissolved, at 0° C., in 130 ml of 1 N aqueous sodiumhydroxide solution (turbid solution), and this solution is acidified topH=5 using 1 N hydrochloric acid. The precipitate is filtered off,washed with water and dried under high vacuum.

Yield: 6.4 g (36% of theory) HPLC: Rt=4.09 min (HPLC method/instrument3) MW 510.55; m/z found: 511 ¹H-NMR (500 MHz, DMSO-d₆): δ=10.42 (s, 1H);9.33 (s, 1H); 8.21 (d, 2H); 7.97 (d, 2H); 7.64 (t, 1H); 7.53 (s, 1H);7.45 (d, 1H); 7.27 (d, 1H); 7.12 (t, 1H); 6.78 (d, 1H); 6.73 (d, 1H);6.57 (s, 2H); 4.48 (d, 2H); 1.21 (s, 6H).

Example 136 Ethyl({6-[3-(4-{[(3-{[(1-methylcyclopropyl)carbonyl]amino}phenyl)amino]-sulphonyl}-phenyl)-1,2,4-oxadiazol-5-yl]-2-pyridinyl}amino)(oxo)-acetate

Under argon, 400 mg (0.82 mmol) of the compound from Example 134 aredissolved in 12 ml of dichloromethane, and 70 mg (0.09 mmol) of pyridineand 150 mg (1.1 mmol) of monoethyl oxalyl chloride are added withstirring. The solution is stirred at room temperature for another 30min. The reaction mixture is then added to 25 ml of pH 7 buffer, theaqueous phase is extracted three times with dichloromethane and thecombined organic phases are washed in each case twice with sat. sodiumchloride solution, sodium bicarbonate solution and sat. sodium chloridesolution. The organic phase is separated off, dried over sodium sulphateand concentrated under reduced pressure. The crude product is purifiedby chromatography on silica gel 60 using the mobile phase toluene/ethylacetate (1:1 v/v).

Yield: 349 mg (72% of theory) HPLC: Rt=4.57 min (HPLC method/instrument3) MW 590.61; m/z found: 591 ¹H-NMR (200 MHz, DMSO-d₆): δ=11.41 (s, 1H);10.42 (s, 1H); 9.20 (s, 1H); 8.28–8.16 (m, 6H); 8.00 (d, 1H); 7.60 (s,1H); 7.28 (d, 1H); 7.13 (t, 1H); 6.79 (d, 1H); 4.32 (q, 2H); 1.37–1.29(m, 6H); 1.08–1.03 (m, 2H); 0.63–0.58 (m, 2H).

Example 137({6-[3-(4-{[(3-{[(1-Methylcyclopropyl)carbonyl]amino}phenyl)amino]sulphonyl}-phenyl)-1,2,4-oxadiazol-5-yl]-2-pyridinyl}amino)(oxo)-aceticacid

152 mg (0.26 mmol) of the compound from Example 136 are taken up in 7.5ml of dioxane, and 0.75 ml (0.75 mmol) of 1 N aqueous sodium hydroxidesolution is added. The mixture is stirred at room temperature for 16 hand then carefully acidified to pH=7 using 1 N hydrochloric acid, andthe solvent is removed under reduced pressure. The crude product ispurified by preparative HPLC (CromSil C18, 250×30 mm, flow rate 50ml/min, runtime 35 min, detection at 254 nm, gradient 10% acetonitrile @3 min->90% acetonitrile @ 31 min->90% acetonitrile @ 34 min->10%acetonitrile @ 34.01 min).

Yield: 35 mg (24% of theory) HPLC: Rt=4.23 min (HPLC method/instrument3) MW 562.56; m/z found: 563 ¹H-NMR (200 MHz, DMSO-d₆): δ=11.71 (s, 1H);10.40 (s, 1H); 9.16 (s, 1H); 8.40 (d, 1H); 8.26 (d, 2H); 8.13 (t, 1H);8.04–7.94 (m, 3H); 7.53 (s, 1H); 7.24 (d, 1H); 7.14 (t, 1H); 6.77 (d,1H); 1.36 (s, 3H); 1.08–1.03 (m, 2H); 0.62–0.57 (m, 2H).

Example 1381-Methyl-N-[3-({[4-(5-{6-[(methylsulphonyl)amino]-2-pyridinyl}-1,2,4-oxadiazol-3-yl)phenyl]sulphonyl}amino)phenyl]cyclopropanecarboxamide

200 mg (0.38 mmol) of the compound from Example 134 are dissolved in 10ml of THF and, under argon, 0.5 ml (6.18 mmol) of pyridine and 90 mg(0.75 mmol) of methanesulphonyl chloride are added. The mixture isstirred at room temperature for 16 h, the solvent is then removed underreduced pressure, the residue is taken up in 5 ml of methanol and againconcentrated under reduced pressure, and the crude product is purifiedby preparative HPLC (CromSil C18, 250×30 mm, flow rate 50 ml/min,runtime 35 min, detection at 254 nm, gradient 10% acetonitrile @ 3min->90% acetonitrile @ 31 min->90% acetonitrile @ 34 min->10%acetonitrile @ 34.01 min).

Yield: 82 mg (30% of theory) HPLC: Rt=4.30 min (HPLC method/instrument3) MW 588.64; m/z found: 589 ¹H-NMR (200 MHz, DMSO-d₆): δ=10.99 (br s,1H); 10.48 (br s, 1H); 9.36 (s, 1H); 8.25 (d, 1H); 8.09–7.96 (m, 4H);7.59–7.57 (m, 1H); 7.33–7.11 (m, 6H); 6.81 (d, 1H); 4.43 (d, 2H); 3.48(s, 3H); 1.27–1.14 (m, 6H).

Further 1,2,4-oxadiazole derivatives attached via position 3 andprepared according to the processes according to the invention arelisted in Table 4:

Ex. m/z HPLC Rt HPLC No. Structure MW found [min] method 139

592 593 2.45 8 140

604 605 2.59 8 141

576 577 2.4 8 142

508 509 2.22 8 143

532 144

586 145

559 560 2.72 8 146

505 506 4.38 3 147

490 148

535 149

561 562 4.05 3 150

610 611 4.59 3 151

513 514 2.49 8 152

616 617 153

672 673 4.61 3 154

492 493 2.79 8

The compounds listed in the working examples and tables werecharacterized using the LC-MS and HPLC methods described below:

Method 1:

Column: Kromasil C18, L-R temperature: 30° C., flow rate=0.75 ml min⁻¹,mobile phase: A=0.01 M HClO₄, B=CH₃CN, gradient:→0.5 min 98% A→4.5 min10% A→6.5 min 10% A

Method 2:

Column: Kromasil C18 60×2 mm, L-R temperature: 30° C., flow rate=0.75 mlmin⁻¹, mobile phase: A=0.01 M H₃PO₄, B=CH₃CN, gradient:→0.5 min 90%A→4.5 min 10% A→6.5 min 10% A

Method 3:

Column: Kromasil C18 60×2 mm, L-R temperature: 30° C., flow rate=0.75 mlmin⁻¹, mobile phase: A=0.005 M HClO₄, B=CH₃CN, gradient:→0.5 min 98%A→4.5 min 10% A→6.5 min 10% A

Method 4:

Column: symmetry C18 2.1×150 mm, column oven: 50° C., flow rate=0.6 mlmin⁻¹, mobile phase: A=0.6 g 30% strength HCl/1 water, B=CH₃CN,gradient: 0.0 min 90% A→4.0 min 10% A→9 min 10% A

Method 5:

LC-MS:MHZ-2Q, Instrument Micromass Quattro LCZ Column: Symmetry C18 50mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate=0.5 ml min⁻¹, mobilephase A=CH₃CN+0.1% formic acid, mobile phase B=water+0.1% formic acid,gradient: 0.0 min 10% A→4 min 90% A→6 min 90% AMethod 6:

LC-MS: MHZ-2P, Instrument Micromass Platform LCZ Column: Symmetry C18 50mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate=0.5 ml min⁻¹, mobilephase A=CH₃CN+0.1% formic acid, mobile phase B=water+0.1% formic acid,gradient: 0.0 min 10% A→4 min 90% A→6 min 90% A

Method 7:

LC-MS: MHZ-7Q, Instrument Micromass Quattro LCZ Column: Symmetry C18 50mm×2.1 mm, 3.5 μm, temperature: 40° C., flow rate=0.5 ml min⁻¹, mobilephase A=CH₃CN+0.1% formic acid, mobile phase B=water+0.1% formic acid,gradient: 0.0 min 5% A→1 min 5% A→5 min 90% A→6 min 90% A

Method 8:

Column: Symmetry C18 2.1×150 mm, column oven: 50° C., flow rate=0.9 mlmin⁻¹, mobile phase: A=0.3 g 30% strength HCl/1 water, B=CH₃CN,gradient: 0.0 min 90% A→3.0 min 10% A→6.0 min 10% A

Method 9:

HP1100, column: LiChroCart 75-5 LiChrospher 100 RP-18 5 μm, column oven:40° C., flow rate=2.5 ml min⁻¹, mobile phase: A=water having 0.05% TFA,B=CH₃CN having 0.05% TFA, gradient: 0.0 min 90% A→0.05 min 90% A→5.0 min5% A→7.0 min 5% A→7.05 min 90% A→8.0 min 90% A

1. A compound of the general formula (I)

in which R² and R³ are identical or different and represent hydrogen,hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,(C₁–C₆)-alkyl, (C₁–C₆)-alkoxy or represent a group of the formula

 in which R⁵, R⁶ and R⁷ are identical or different and each representshydrogen or (C₁–C₆)-alkyl which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy, A represents five-or six-membered heteroaryl, which is attached to the adjacent phenylring via a C atom and has one to three heteroatoms selected from thegroup consisting of N, O and S, R¹ represents (C₆–C₁₀)-aryl, 5- to10-membered heteroaryl or 5- to 10-membered heterocyclyl having in eachcase one to three heteroatoms selected from the group consisting of N, Oand S, where R¹ may be substituted by up to three substituents selectedfrom the group consisting of hydroxyl, amino, mono-(C₁–C₆)-alkylamino,di-(C₁–C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁–C₆)-alkyl whichfor its part may be substituted by amino or hydroxyl, (C₁–C₆)-alkoxy,phenyl, 5- or 6-membered heterocyclyl having up to two heteroatomsselected from the group consisting of N, O and S, 5- or 6-memberedheteroaryl having one or more heteroatoms selected from the groupconsisting of N, O and S, —C(O)—O—R⁸, —C(O)—NR⁹R¹⁰, —NH—C(O)—R¹¹,—NH—C(O)—C(O)—R¹² and —NH—SO₂—R¹³, where R⁸, R⁹ and R¹⁰ are identical ordifferent and each represents hydrogen or (C₁–C₆)-alkyl, or R⁹ and R¹⁰together with the nitrogen atom to which they are attached form a 5- or6-membered heterocycle which may contain a further nitrogen or oxygenheteroatom and which may be mono- or disubstituted by identical ordifferent substituents from the group consisting of (C₁–C₄)-alkyl whichfor its part is optionally substituted by hydroxyl or amino, amino,hydroxyl, (C₁–C₄)-alkoxy, oxo, carboxyl and (C₁–C₄)-alkoxycarbonyl, R¹¹and R¹² are identical or different and each represents trifluoromethyl,(C₁–C₆)-alkoxy, or hydroxyl or represents (C₁–C₆)-alkyl which isoptionally mono- or disubstituted by identical or different constituentsfrom the group consisting of amino, (C₁–C₆)-alkoxycarbonylamino,mono-(C₁–C₆)-acylamino, hydroxyl, amidino, guanidino,(C₁–C₆)-alkoxycarbonyl, carboxyl and phenyl, and R¹³ represents(C₁–C₆)-alkyl or (C₆–C₁₀)-aryl which may in each case be substituted byhalogen, amino, hydroxyl, (C₁–C₄)-alkoxy or (C₁–C₄)-alkyl, R⁴ represents(C₁–C₆)-alkyl which may be substituted up to three times by identical ordifferent substituents from the group consisting of amino, hydroxyl,halogen, (C₁–C₆)-alkoxy, (C₁–C₅)-alkanoyloxy and phenyl, which for itspart is optionally mono- or disubstituted by identical or differentsubstituents from the group consisting of halogen, nitro, cyano, aminoand hydroxyl, or represents (C₃–C₇)-cycloalkyl which may be substitutedup to three times by identical or different substituents from the groupconsisting of amino, hydroxyl, halogen, (C₁–C₆)-alkoxy and(C₁–C₆)-alkyl, which for its part is optionally substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, halogen and (C₁–C₆)-alkoxy, or represents(C₆–C₁₀)-aryl which is optionally mono- or disubstituted by identical ordifferent substituents from the group consisting of halogen, nitro,cyano, amino and hydroxyl, and in which X represents oxygen or sulphur,and in which nitrogen-containing heterocycles may also be present asN-oxides, or a tautomer, steroisomer, mixture of steroisomer, orpharmacologically acceptable salt thereof.
 2. The compound of thegeneral formula (I) according to claim 1, in which R² and R³ areidentical or different and represent hydrogen, hydroxyl, halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, (C₁–C₆)-alkyl, (C₁–C₆)-alkoxyor represent a group of the formula

 in which R⁵, R⁶ and R⁷ are identical or different and each representshydrogen of (C₁–C₆)-alkyl, which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy, A represents five-or six-membered heteroaryl, which is attached to the adjacent phenylring via a C atom and has one to three heteroatoms selected from thegroup consisting of N, O and S, R¹ represents (C₆–C₁₀)-aryl, 5- to10-membered heteroaryl or 5- to 10-membered heterocyclyl having in eachcase one to three heteroatoms selected from the group consisting of N, Oand S, where R¹ may be substituted by up to three substituents selectedfrom the group consisting of hydroxyl, amino, mono-(C₁–C₆)-alkylamino,di-(C₁–C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁–C₆)-alkyl whichfor its part may be substituted by amino or hydroxyl, (C₁–C₆)-alkoxy,phenyl, 5- or 6-membered heteroaryl having one or more heteroatomsselected from the group consisting of N, O and S, —C(O)—O—R⁸,—C(O)—NR⁹R¹⁰ and —NH—C(O)—R¹¹, where R⁸, R⁹ and R¹⁰ are identical ordifferent and each represents hydrogen or (C₁–C₆)-alkyl, and R¹¹represents (C₁–C₆)-alkyl which is optionally mono- or disubstituted byidentical or different substituents from the group consisting of amino,hydroxyl, guanidino, carboxyl and phenyl, R⁴ represents (C₁–C₆)-alkylwhich may be substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, halogen,(C₁–C₆)-alkoxy and phenyl, which for its part is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl, represents(C₃–C₇)-cycloalkyl which may be substituted up to three times byidentical or different substituents from the group consisting of amino,hydroxyl, halogen, (C₁–C₆)-alkoxy and (C₁–C₆)-alkyl, which for its partis optionally substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, halogen and(C₁–C₆)-alkoxy, or represents (C₆–C₁₀)-aryl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl, and in which Xrepresents oxygen or sulphur, and in which nitrogen-containingheterocycles may also be present as N-oxides, or a tautomer,stereoisomer, mixture of stereoisomers, or pharmacologically acceptablesalt thereof.
 3. The compound of the general formula (I) according toclaim 1, in which R² and R³ are identical or different and representhydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy or represent a group ofthe formula

 in which R⁵, R⁶ and R⁷ are identical or different and each representshydrogen or (C₁–C₆)-alkyl, which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy, A represents five-or six-membered heteroaryl, which is attached to the adjacent phenylring, via a C atom and has one to three heteroatoms selected from thegroup consisting of N, O and S, R¹ represents (C₆–C₁₀)-aryl, 5- to10-membered heteroaryl or 5- to 10-membered heterocyclyl having in eachcase one to three heteroatoms selected from the group consisting of N, Oand S, where R¹ may be substituted by up to three substituents selectedfrom the group consisting of hydroxyl, amino, mono-(C₁–C₆)-alkylamino,di-(C₁–C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁–C₆)-alkyl whichfor its part may be substituted by amino or hydroxyl, (C₁–C₆)-alkoxy,phenyl, 5- or 6-membered heteroaryl having one or more heteroatomsselected from the group consisting of N, O and S, —C(O)—O—R⁸,—C(O)—NR⁹R¹⁰ and —NH—C(O)—R¹¹, where R⁸, R⁹ and R¹⁰ are identical ordifferent and each represents hydrogen or (C₁–C₆)-alkyl, and R¹¹represents (C₁–C₆)-alkyl, which is optionally mono- or disubstituted byidentical or different substituents from the group consisting of amino,hydroxyl, guanidino, carboxyl and phenyl, R⁴ represents (C₁–C₆)-alkylwhich may be substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, halogen,(C₁–C₆)-alkoxy and phenyl, which for its part is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl, represents(C₃–C₇)-cycloalkyl which may be substituted up to three times byidentical or different substituents from the group consisting of amino,hydroxyl, halogen, (C₁–C₆)-alkoxy and (C₁–C₆)-alkyl, which for its partis optionally substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, halogen and(C₁–C₆)-alkoxy, or represents (C₆–C₁₀)-aryl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl, and in which Xrepresents oxygen, and in which nitrogen-containing heterocycles mayalso be present as N-oxides, or a tautomer, stereoisomer, mixture ofstereoisomers, or pharmacologically acceptable salt thereof.
 4. Thecompounds of the general formula (I) according to claim 1, in which R²and R³ are identical or different and represent hydrogen or halogen, Arepresents the radical (A-I)

 which is attached to the adjacent phenyl ring via one of the carbonatoms in position 3 or 5,  and in which Y represents oxygen or sulphur,or A represents the radical (A-II)

 which is attached to the adjacent phenyl ring via one of the carbonatoms in position 2 or 5,  and in which Y represents oxygen or sulphur,R¹ represents 5- to 10-membered heteroaryl or 5- or 10-memberedheterocyclyl having in each case up to three heteroatoms selected fromthe group consisting of N, O and S, or represents phenyl, where R¹ maybe substituted by one to three substituents selected from the groupconsisting of (C₁–C₄)-alkyl which for its part is optionally substitutedby hydroxyl or amino, hydroxyl, oxo, halogen, amino,mono-(C₁–C₄)-alkylamino, di-(C₁–C₄)-alkylamino and —NH—C(O)—R¹¹, whereR¹¹ represents (C₁–C₆)-alkyl which is optionally mono- or disubstitutedby identical or different substituents from the group consisting ofamino, hydroxyl, guanidino and carboxyl, R⁴ represents (C₁–C₄)-alkylwhich may be substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, fluorine,chlorine and (C₁–C₄)alkoxy, or represents (C₃–C₅)-cycloalkyl, which maybe substituted up to three times by identical or different substituentsfrom the group consisting of amino, hydroxyl, fluorine, chlorine,(C₁–C₄)-alkoxy and (C₁–C₄)-alkyl, which for its part is optionallysubstituted up to three times by identical or different substituentsfrom the group consisting of amino, hydroxyl, fluorine, chlorine and(C₁–C₄)-alkoxy, and in which X represents oxygen or sulphur, and inwhich nitrogen-containing heterocycles may also be present as N-oxides,or a tautomer, stereoisomer, mixture of stereoisomers, orpharmacologically acceptable salt thereof.
 5. The compound of thegeneral formula (I) according to claim 1, in which R² and R³ areidentical or different and represent hydrogen or halogen, A representsthe radical (A-I)

 which is attached to the adjacent phenyl ring via one of the carbonatoms in position 3 or 5,  and in which Y represents oxygen or sulphur,or A represents the radical (A-II)

 which is attached to the adjacent phenyl ring via one of the carbonatoms in position 2 or 5,  and in which Y represents oxygen or sulphur,R¹ represents 5- to 10-membered heteroaryl or 5- or 10-memberedheterocyclyl having in each case up to three heteroatoms selected fromthe group consisting of N, O and S, or represents phenyl, where R¹ maybe substituted by one to three substituents selected from the groupconsisting of (C₁–C₄)-alkyl which for its-part is optionally substitutedby hydroxyl or amino, hydroxyl, oxo, halogen, amino,mono-(C₁–C₄)-alkylamino, di-(C₁–C₄)-alkylamino and —NH—C(O)—R¹¹, whereR¹¹ represents (C₁–C₆)-alkyl which is optionally mono- or disubstitutedby identical or different substituents from the group consisting ofamino, hydroxyl, guanidino and carboxyl, R⁴ represents (C₁–C₄)-alkylwhich may be substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, fluorine,chlorine and (C₁–C₄)-alkoxy, or represents (C₃–C₅)-cycloalkyl which maybe substituted up to three times by identical or different substituentsfrom the group consisting of amino, hydroxyl, fluorine, chlorine,(C₁–C₄)-alkoxy and (C₁–C₄)-alkyl, which for its part is optionallysubstituted up to three times by identical or different substituentsfrom the group consisting of amino, hydroxyl, fluorine, chlorine and(C₁–C₄)-alkoxy, and in which X represents oxygen, or a tautomer,stereoisomer, mixture of stereoisomers, or pharmacologically acceptablesalt thereof.
 6. The compound of the general formula (I) according toclaim 1, in which R² and R³ represent hydrogen, A represents one of theradicals

R¹ represents a radical selected from the group consisting of phenyl,pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl,oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl, where R¹ may besubstituted by one or two substituents selected from the groupconsisting of methyl, aminomethyl, hydroxyl, bromine, chlorine,fluorine, amino, dimethylamino and —NH—C(O)—R¹¹, where R¹¹ represents(C₁–C₆)-alkyl which is optionally mono- or disubstituted by identical ordifferent substituents from the group consisting of amino, hydroxyl,guanidino and carboxyl, R⁴ represents tert-butyl which is optionallysubstituted up to three times by identical or different substituentsfrom the group consisting of hydroxyl, fluorine and chlorine, orrepresents cyclopropyl or cyclobutyl which are substituted by methyl,which for its part is optionally substituted by hydroxyl, fluorine orchlorine, and in which X represents oxygen, and in whichnitrogen-containing heterocycles may also be present as N-oxides, or atautomer, stereoisomer, mixture of stereoisomers, or pharmacologicallyacceptable salt thereof.
 7. The compounds of the general formula (I)according to claim 1, in which R² and R³ represent hydrogen, Arepresents one of the radicals

R¹ represents a radical selected from the group consisting of phenyl,pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl,oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl, where R¹ may besubstituted by one or two substituents selected from the groupconsisting of methyl, aminomethyl, hydroxyl, bromine, chlorine,fluorine, amino, dimethylamino and —NH—C(O)—R¹¹, where R¹¹ represents(C₁–C₆)-alkyl which is optionally mono- or disubstituted by identical ordifferent substituents from the group consisting of amino, hydroxyl,guanidino and carboxyl, R⁴ represents tert-butyl which is optionallysubstituted up to three times by identical or different substituentsfrom the group consisting of hydroxyl, fluorine and chlorine, orrepresents cyclopropyl or cyclobutyl which are substituted by methyl,which for its part is optionally substituted by hydroxyl, fluorine orchlorine, and in which X represents oxygen.
 8. The compound according toclaim 1 of the general formula (Ia)

in which R¹, R⁴, A and X are as defined in claim 1, and R² and R³ areidentical or different and represent hydrogen, hydroxyl, halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, (C₁–C₆)-alkyl or(C₁–C₆)-alkoxy.
 9. The compound of the general formula (I) according toclaim 1, in which R⁴ represents the radical


10. The compound of the general formula (I) according to claim 1, inwhich A represents a 1,2,4-oxadiazole attached via the 3-position. 11.The compound according to claim 1, selected from the group consisting ofthe following compounds:


12. A process for preparing compounds of the general formula (I)according to claim 1, in which A represents the radical (A-I)

 which is attached to the adjacent phenyl ring via one of the carbonatoms in position 3 or 5, and in which Y represents oxygen, by reactingan amidoxime of the general formula (D-1)

 in which X, R², R³ and R⁴ are as defined in claim 1, with a carboxylicacid (E-1)R¹—COOH  (E-1)  in which R¹ is as defined in claim 1, or  condensing asulphonamide of the general formula (F-3)

 in which X, R², R³ and R⁴ are as defined in claim 1, with an amidoximeof the general formula (G-1)

 in which R¹ is as defined in claim 1, giving a compound of the generalformula (G-2)

 in which R¹, R², R³, R⁴ and X are as defined in claim 1,  andsubsequently cyclizing the compound (G-2) with elimination of water,giving the compound of the general formula (I).
 13. A process forpreparing compounds of the general formula (I) according to claim 1 inwhich A represents the radical (A-II)

 which is attached to the adjacent phenyl ring via one of the carbonatoms in position 2 or 5,  and in which Y represents oxygen, bycyclizing a hydrazide of the general formula (H-2)

 in which X, R¹, R², R³ and R⁴ are as defined in claim 1, and FHrepresents hydrogen, an amino protective group or a polymeric support,with elimination of water, to give a compound of the general formula(I).
 14. A process for preparing compounds of the general formula (I)according to claim 1, in which X represents oxygen, A represents theradical (A-II)

 which is attached to the adjacent phenyl ring via one of the carbonatoms of position 2 or 5,  and in which Y represents sulphur, bycyclizing a hydrazide of the general formula (H-3)

 in which R¹, R², R³ are as defined in claim 1, FH represents hydrogen,an amino protective group or a polymeric support, and R^(4′) represents(C₁–C₆)-alkoxy, (C₁–C₆)-alkenoxy or aralkoxy,  in the presence of a thiodonor, to give a compound of the general formula (I) in which Yrepresents sulphur, then removing group —C(O)—R^(4′) and finallyreacting with a compound of the general formula

 in which R⁴ is as defined in claim 1 and O represents a leaving group.15. The process of claim 14 wherein said thio donor is Lawesson'sreagent.
 16. The process of claim 14 wherein said leaving group Q ishalogen.
 17. The process of claim 16 wherein said halogen is chlorine orbromine.
 18. A method for treating cytomegalovirus infections comprisingadministering an effective amount of a compound of claim
 1. 19. Apharmaceutical composition, comprising a compound of the general formula(I) according to claim 1 and a pharmaceutically acceptable carrier. 20.A compound of the general formula (Ia) according to claim 1

in which R¹, R², R³, R⁴, A and X are as defined in claim 1.